The Progress of Small Molecule Targeting BCR-ABL in the Treatment of
Chronic Myeloid Leukemia

Yuan      Zhang; Xin      Wu; Xueyan      Sun; Jun      Yang; Chang      Liu; Guotao      Tang; Xiaoyong      Lei; Honglin      Huang; Junmei      Peng
Abstract

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease. According to the American Cancer Society's 2021 cancer data report, new cases of CML account for about 15% of all leukemias. CML is generally divided into three stages: chronic phase, accelerated phase, and blast phase. Nearly 90% of patients are diagnosed as a chronic phase. Allogeneic stem cell transplantation and chemotherapeutic drugs, such as interferon IFN-α were used as the earliest treatments for CML. However, they could generate obvious side effects, and scientists had to seek new treatments for CML. A new era of targeted therapy for CML began with the introduction of imatinib, the first-generation BCR-ABL kinase inhibitor. However, the ensuing drug resistance and mutant strains led by T315I limited the further use of imatinib. With the continuous advancement of research, tyrosine kinase inhibitors (TKI) and BCR-ABL protein degraders with novel structures and therapeutic mechanisms have been discovered. From biological macromolecules to classical target protein inhibitors, a growing number of compounds are being developed to treat chronic myelogenous leukemia. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in CML therapy, including TKIs and BCR-ABL protein degrader. The examples provided herein describe the pharmacology activity of small-molecule drugs. These drugs will provide new enlightenment for future treatment directions.
Graphical Abstract

[1]
Rowley, J.D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and giemsa staining. Nature,  1973, 243(5405), 290-293.
 [http://dx.doi.org/10.1038/243290a0] [PMID: 4126434]

[2]
Voncken, J.W.; Kaartinen, V.; Pattengale, P.K.; Germeraad, W.T.; Groffen, J.; Heisterkamp, N. BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood,  1995, 86(12), 4603-4611.
 [http://dx.doi.org/10.1182/blood.V86.12.4603.bloodjournal86124603] [PMID: 8541551]

[3]
Epstein, F.H.; Kurzrock, R.; Gutterman, J.U.; Talpaz, M. The molecular genetics of philadelphia chromosome-positive leukemias. N. Engl. J. Med.,  1988, 319(15), 990-998.
 [http://dx.doi.org/10.1056/NEJM198810133191506] [PMID: 3047582]

[4]
Melo, J.V.; Barnes, D.J. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat. Rev. Cancer,  2007, 7(6), 441-453.
 [http://dx.doi.org/10.1038/nrc2147] [PMID: 17522713]

[5]
Clarkson, B.; Strife, A.; Wisniewski, D.; Lambek, C.L.; Liu, C. Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies. Leukemia,  2003, 17(7), 1211-1262.
 [http://dx.doi.org/10.1038/sj.leu.2402912] [PMID: 12835715]

[6]
Innes, A.J.; Milojkovic, D.; Apperley, J.F. Allogeneic transplantation for CML in the TKI era: Striking the right balance. Nat. Rev. Clin. Oncol.,  2016, 13(2), 79-91.
 [http://dx.doi.org/10.1038/nrclinonc.2015.193] [PMID: 26573423]

[7]
Weisdorf, D.J.; Anasetti, C.; Antin, J.H.; Kernan, N.A.; Kollman, C.; Snyder, D.; Petersdorf, E.; Nelson, G.; McGlave, P. Allogeneic bone marrow transplantation for chronic myelogenous leukemia: Comparative analysis of unrelated versus matched sibling donor transplantation. Blood,  2002, 99(6), 1971-1977.
 [http://dx.doi.org/10.1182/blood.V99.6.1971] [PMID: 11877268]

[8]
Champlin, R.; Jabbour, E.; Kebriaei, P.; Anderlini, P.; Andersson, B.; de Lima, M. Allogeneic stem cell transplantation for chronic myeloid leukemia resistant to tyrosine kinase inhibitors. Clin. Lymphoma Myeloma Leuk.,  2011, 11(Suppl. 1), S96-S100.
 [http://dx.doi.org/10.1016/j.clml.2011.03.028] [PMID: 22035758]

[9]
Ben-Bassat, I.; Raanani, P.; Gale, R.P. Graft-versus-leukemia in chronic lymphocytic leukemia. Bone Marrow Transplant.,  2007, 39(8), 441-446.
 [http://dx.doi.org/10.1038/sj.bmt.1705619] [PMID: 17322931]

[10]
Hehlmann, R.; Heimpel, H.; Hasford, J.; Kolb, H.J.; Pralle, H.; Hossfeld, D.K.; Queisser, W.; Löffler, H.; Hochhaus, A.; Heinze, B. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group see comments. Blood,  1994, 84(12), 4064-4077.
 [http://dx.doi.org/10.1182/blood.V84.12.4064.bloodjournal84124064] [PMID: 7994025]

[11]
Wetzler, M.; Kantarjian, H.; Kurzrock, R.; Talpaz, M. Interferon-α therapy for chronic myelogenous leukemia. Am. J. Med.,  1995, 99(4), 402-411.
 [http://dx.doi.org/10.1016/S0002-9343(99)80189-2] [PMID: 7573097]

[12]
Goldman, J.M. Treatment strategies for CML. Best Pract. Res. Clin. Haematol.,  2009, 22(3), 303-313.
 [http://dx.doi.org/10.1016/j.beha.2009.08.001] [PMID: 19959082]

[13]
Shah, N.P.; Tran, C.; Lee, F.Y.; Chen, P.; Norris, D.; Sawyers, C.L. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science,  2004, 305(5682), 399-401.
 [http://dx.doi.org/10.1126/science.1099480] [PMID: 15256671]

[14]
Verstovsek, S.; Giles, F.J.; Quintás-Cardama, A.; Manshouri, T.; Huynh, L.; Manley, P.; Cortes, J.; Tefferi, A.; Kantarjian, H. Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-α-expressing cells. Leuk. Res.,  2006, 30(12), 1499-1505.
 [http://dx.doi.org/10.1016/j.leukres.2006.03.012] [PMID: 16682077]

[15]
O’Hare, T.; Shakespeare, W.C.; Zhu, X.; Eide, C.A.; Rivera, V.M.; Wang, F.; Adrian, L.T.; Zhou, T.; Huang, W.S.; Xu, Q.; Metcalf, C.A., III; Tyner, J.W.; Loriaux, M.M.; Corbin, A.S.; Wardwell, S.; Ning, Y.; Keats, J.A.; Wang, Y.; Sundaramoorthi, R.; Thomas, M.; Zhou, D.; Snodgrass, J.; Commodore, L.; Sawyer, T.K.; Dalgarno, D.C.; Deininger, M.W.N.; Druker, B.J.; Clackson, T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell,  2009, 16(5), 401-412.
 [http://dx.doi.org/10.1016/j.ccr.2009.09.028] [PMID: 19878872]

[16]
Puttini, M.; Coluccia, A.M.L.; Boschelli, F.; Cleris, L.; Marchesi, E.; Donella-Deana, A.; Ahmed, S.; Redaelli, S.; Piazza, R.; Magistroni, V.; Andreoni, F.; Scapozza, L.; Formelli, F.; Gambacorti-Passerini, C. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res.,  2006, 66(23), 11314-11322.
 [http://dx.doi.org/10.1158/0008-5472.CAN-06-1199] [PMID: 17114238]

[17]
Balabanov, S.; Braig, M.; Brümmendorf, T.H. Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discov. Today. Technol.,  2014, 11, 89-99.
 [http://dx.doi.org/10.1016/j.ddtec.2014.03.003] [PMID: 24847658]

[18]
Bondeson, D.P.; Smith, B.E.; Burslem, G.M.; Buhimschi, A.D.; Hines, J.; Jaime-Figueroa, S.; Wang, J.; Hamman, B.D.; Ishchenko, A.; Crews, C.M. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol.,  2018, 25(1), 78-87.e5.
 [http://dx.doi.org/10.1016/j.chembiol.2017.09.010] [PMID: 29129718]

[19]
Demizu, Y.; Okuhira, K.; Motoi, H.; Ohno, A.; Shoda, T.; Fukuhara, K.; Okuda, H.; Naito, M.; Kurihara, M. Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy. Bioorg. Med. Chem. Lett.,  2012, 22(4), 1793-1796.
 [http://dx.doi.org/10.1016/j.bmcl.2011.11.086] [PMID: 22277276]

[20]
Buhimschi, A.D.; Armstrong, H.A.; Toure, M.; Jaime-Figueroa, S.; Chen, T.L.; Lehman, A.M.; Woyach, J.A.; Johnson, A.J.; Byrd, J.C.; Crews, C.M. Targeting the C481S ibrutinib-resistance mutation in Bruton’s Tyrosine kinase using PROTAC-mediated degradation. Biochemistry,  2018, 57(26), 3564-3575.
 [http://dx.doi.org/10.1021/acs.biochem.8b00391] [PMID: 29851337]

[21]
Burslem, G.M.; Smith, B.E.; Lai, A.C.; Jaime-Figueroa, S.; McQuaid, D.C.; Bondeson, D.P.; Toure, M.; Dong, H.; Qian, Y.; Wang, J.; Crew, A.P.; Hines, J.; Crews, C.M. The advantages of targeted protein degradation over inhibition: An RTK case study. Cell Chem. Biol.,  2018, 25(1), 67-77.e3.
 [http://dx.doi.org/10.1016/j.chembiol.2017.09.009] [PMID: 29129716]

[22]
Itoh, Y.; Ishikawa, M.; Naito, M.; Hashimoto, Y. Protein knockdown using methyl bestatin-ligand hybrid molecules: Design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J. Am. Chem. Soc.,  2010, 132(16), 5820-5826.
 [http://dx.doi.org/10.1021/ja100691p] [PMID: 20369832]

[23]
Ohoka, N.; Ujikawa, O.; Shimokawa, K.; Sameshima, T.; Shibata, N.; Hattori, T.; Nara, H.; Cho, N.; Naito, M. Different degradation mechanisms of inhibitor of apoptosis proteins (IAPs) by the specific and nongenetic IAP-dependent protein eraser (SNIPER). Chem. Pharm. Bull.,  2019, 67(3), 203-209.
 [http://dx.doi.org/10.1248/cpb.c18-00567] [PMID: 30369550]

[24]
Ohoka, N.; Nagai, K.; Hattori, T.; Okuhira, K.; Shibata, N.; Cho, N.; Naito, M. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway. Cell Death Dis.,  2014, 5(11), e1513.
 [http://dx.doi.org/10.1038/cddis.2014.471] [PMID: 25375378]

[25]
Li, Y.; Geng, J.; Liu, Y.; Yu, S.; Zhao, G. Thiadiazole-a promising structure in medicinal chemistry. ChemMedChem,  2013, 8(1), 27-41.
 [http://dx.doi.org/10.1002/cmdc.201200355] [PMID: 23208773]

[26]
Jain, A.K.; Sharma, S.; Vaidya, A.; Ravichandran, V.; Agrawal, R.K. 1,3,4-thiadiazole and its derivatives: A review on recent progress in biological activities. Chem. Biol. Drug Des.,  2013, 81(5), 557-576.
 [http://dx.doi.org/10.1111/cbdd.12125] [PMID: 23452185]

[27]
Morigi, R.; Locatelli, A.; Leoni, A.; Rambaldi, M. Recent patents on thiazole derivatives endowed with antitumor activity. Recent Patents Anticancer Drug Discov.,  2015, 10(3), 280-297.
 [http://dx.doi.org/10.2174/1574892810666150708110432] [PMID: 26152151]

[28]
Haider, S.; Alam, M.S.; Hamid, H. 1,3,4-Thiadiazoles: A potent multi targeted pharmacological scaffold. Eur. J. Med. Chem.,  2015, 92, 156-177.
 [http://dx.doi.org/10.1016/j.ejmech.2014.12.035] [PMID: 25553540]

[29]
Dawood, K.M.; Farghaly, T.A. Thiadiazole inhibitors: A patent review. Expert Opin. Ther. Pat.,  2017, 27(4), 477-505.
 [http://dx.doi.org/10.1080/13543776.2017.1272575] [PMID: 27976971]

[30]
Radi, M.; Crespan, E.; Botta, G.; Falchi, F.; Maga, G.; Manetti, F.; Corradi, V.; Mancini, M.; Santucci, M.A.; Schenone, S.; Botta, M. Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg. Med. Chem. Lett.,  2008, 18(3), 1207-1211.
 [http://dx.doi.org/10.1016/j.bmcl.2007.11.112] [PMID: 18078752]

[31]
Albert, D.H.; Tapang, P.; Magoc, T.J.; Pease, L.J.; Reuter, D.R.; Wei, R.Q.; Li, J.; Guo, J.; Bousquet, P.F.; Ghoreishi-Haack, N.S.; Wang, B.; Bukofzer, G.T.; Wang, Y.C.; Stavropoulos, J.A.; Hartandi, K.; Niquette, A.L.; Soni, N.; Johnson, E.F.; McCall, J.O.; Bouska, J.J.; Luo, Y.; Donawho, C.K.; Dai, Y.; Marcotte, P.A.; Glaser, K.B.; Michaelides, M.R.; Davidsen, S.K. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther.,  2006, 5(4), 995-1006.
 [http://dx.doi.org/10.1158/1535-7163.MCT-05-0410] [PMID: 16648571]

[32]
Choi, W.K.; El-Gamal, M.I.; Choi, H.S.; Baek, D.; Oh, C.H. New diarylureas and diarylamides containing 1,3,4-triarylpyrazole scaffold: Synthesis, antiproliferative evaluation against melanoma cell lines, ERK kinase inhibition, and molecular docking studies. Eur. J. Med. Chem.,  2011, 46(12), 5754-5762.
 [http://dx.doi.org/10.1016/j.ejmech.2011.08.013] [PMID: 22014559]

[33]
Li, Y.; Tan, C.; Gao, C.; Zhang, C.; Luan, X.; Chen, X.; Liu, H.; Chen, Y.; Jiang, Y. Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors. Bioorg. Med. Chem.,  2011, 19(15), 4529-4535.
 [http://dx.doi.org/10.1016/j.bmc.2011.06.022] [PMID: 21724404]

[34]
Liu, L.; Cao, Y.; Chen, C.; Zhang, X.; McNabola, A.; Wilkie, D.; Wilhelm, S.; Lynch, M.; Carter, C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res.,  2006, 66(24), 11851-11858.
 [http://dx.doi.org/10.1158/0008-5472.CAN-06-1377] [PMID: 17178882]

[35]
Zhao, C.; Wang, R.; Li, G.; Xue, X.; Sun, C.; Qu, X.; Li, W. Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines. Bioorg. Med. Chem. Lett.,  2013, 23(7), 1989-1992.
 [http://dx.doi.org/10.1016/j.bmcl.2013.02.034] [PMID: 23454017]

[36]
Hochhaus, A.; Baccarani, M.; Silver, R.T.; Schiffer, C.; Apperley, J.F.; Cervantes, F.; Clark, R.E.; Cortes, J.E.; Deininger, M.W.; Guilhot, F.; Hjorth-Hansen, H.; Hughes, T.P.; Janssen, J.J.W.M.; Kantarjian, H.M.; Kim, D.W.; Larson, R.A.; Lipton, J.H.; Mahon, F.X.; Mayer, J.; Nicolini, F.; Niederwieser, D.; Pane, F.; Radich, J.P.; Rea, D.; Richter, J.; Rosti, G.; Rousselot, P.; Saglio, G.; Saußele, S.; Soverini, S.; Steegmann, J.L.; Turkina, A.; Zaritskey, A.; Hehlmann, R. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia,  2020, 34(4), 966-984.
 [http://dx.doi.org/10.1038/s41375-020-0776-2] [PMID: 32127639]

[37]
Lombardo, L.J.; Lee, F.Y.; Chen, P. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem.,  2004, 47, 6658-6661.

[38]
Olivieri, A.; Manzione, L. Dasatinib: A new step in molecular target therapy. Ann. Oncol.,  2007, 18(Suppl. 6), vi42-vi46.
 [http://dx.doi.org/10.1093/annonc/mdm223] [PMID: 17591830]

[39]
Li, W.; Chu, J.; Fan, T.; Zhang, W.; Yao, M.; Ning, Z.; Wang, M.; Sun, J.; Zhao, X.; Wen, A. Design and synthesis of novel 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4-thiadiazol- 2-yl)urea derivatives with potent anti-CML activity throughout PI3K/AKT signaling pathway. Bioorg. Med. Chem. Lett.,  2019, 29(14), 1831-1835.
 [http://dx.doi.org/10.1016/j.bmcl.2019.05.005] [PMID: 31097376]

[40]
Altıntop, M.; Ciftci, H.; Radwan, M.; Sever, B.; Kaplancıklı, Z.; Ali, T.; Koga, R.; Fujita, M.; Otsuka, M.; Özdemir, A. Design, synthesis, and biological evaluation of novel 1,3,4- thiadiazole derivatives as potential antitumor agents against chronic myelogenous leukemia: Striking effect of nitrothiazole moiety. Molecules,  2017, 23(1), 59.
 [http://dx.doi.org/10.3390/molecules23010059] [PMID: 29280989]

[41]
Zeytün, E.; Altıntop, M.D.; Sever, B.; Özdemir, A.; Ellakwa, D.E.; Ocak, Z.; Ciftci, H.I.; Otsuka, M.; Fujita, M.; Radwan, M.O. A new series of antileukemic agents: Design, synthesis, in vitro and in silico evaluation of thiazole-based ABL1 kinase inhibitors. Anticancer. Agents Med. Chem.,  2021, 21(9), 1099-1109.
 [http://dx.doi.org/10.2174/1871520620666200824100408] [PMID: 32838725]

[42]
Jordheim, L.P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat. Rev. Drug Discov.,  2013, 12(6), 447-464.
 [http://dx.doi.org/10.1038/nrd4010] [PMID: 23722347]

[43]
Clercq, E.D. Antivirals and antiviral strategies. Nat. Rev. Microbiol.,  2004, 2(9), 704-720.
 [http://dx.doi.org/10.1038/nrmicro975] [PMID: 15372081]

[44]
Seley-Radtke, K.L.; Yates, M.K. The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold. Antiviral Res.,  2018, 154, 66-86.
 [http://dx.doi.org/10.1016/j.antiviral.2018.04.004] [PMID: 29649496]

[45]
Mirza, A.Z. Advancement in the development of heterocyclic nucleosides for the treatment of cancer: A review. Nucleo. Nucleo. Nucleic Acids,  2019, 38(11), 836-857.
 [http://dx.doi.org/10.1080/15257770.2019.1615623] [PMID: 31135268]

[46]
De Clercq, E.; Li, G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev.,  2016, 29(3), 695-747.
 [http://dx.doi.org/10.1128/CMR.00102-15] [PMID: 27281742]

[47]
Fried, M.W.; Shiffman, M.L.; Reddy, K.R.; Smith, C.; Marinos, G.; Gonçales, F.L., Jr; Häussinger, D.; Diago, M.; Carosi, G.; Dhumeaux, D.; Craxi, A.; Lin, A.; Hoffman, J.; Yu, J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med.,  2002, 347(13), 975-982.
 [http://dx.doi.org/10.1056/NEJMoa020047] [PMID: 12324553]

[48]
Kantarjian, H.; Issa, J.P.J.; Rosenfeld, C.S.; Bennett, J.M.; Albitar, M.; DiPersio, J.; Klimek, V.; Slack, J.; de Castro, C.; Ravandi, F.; Helmer, R., III; Shen, L.; Nimer, S.D.; Leavitt, R.; Raza, A.; Saba, H. Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer,  2006, 106(8), 1794-1803.
 [http://dx.doi.org/10.1002/cncr.21792] [PMID: 16532500]

[49]
Furuta, Y.; Takahashi, K.; Kuno-Maekawa, M.; Sangawa, H.; Uehara, S.; Kozaki, K.; Nomura, N.; Egawa, H.; Shiraki, K. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother.,  2005, 49(3), 981-986.
 [http://dx.doi.org/10.1128/AAC.49.3.981-986.2005] [PMID: 15728892]

[50]
Marzag, H.; Zerhouni, M.; Tachallait, H.; Demange, L.; Robert, G.; Bougrin, K.; Auberger, P.; Benhida, R. Modular synthesis of new C-aryl-nucleosides and their anti-CML activity. Bioorg. Med. Chem. Lett.,  2018, 28(10), 1931-1936.
 [http://dx.doi.org/10.1016/j.bmcl.2018.03.063] [PMID: 29655981]

[51]
Dzubak, P.; Hajduch, M.; Vydra, D.; Hustova, A.; Kvasnica, M.; Biedermann, D.; Markova, L.; Urban, M.; Sarek, J. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat. Prod. Rep.,  2006, 23(3), 394-411.
 [http://dx.doi.org/10.1039/b515312n] [PMID: 16741586]

[52]
Laszczyk, M. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med.,  2009, 75(15), 1549-1560.
 [http://dx.doi.org/10.1055/s-0029-1186102] [PMID: 19742422]

[53]
Lu, Z.; Jin, Y.; Qiu, L.; Lai, Y.; Pan, J. Celastrol, a novel HSP90 inhibitor, depletes Bcr–Abl and induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation. Cancer Lett.,  2010, 290(2), 182-191.
 [http://dx.doi.org/10.1016/j.canlet.2009.09.006] [PMID: 19819619]

[54]
Radwan, M.O.; Ismail, M.A.H.; El-Mekkawy, S.; Ismail, N.S.M.; Hanna, A.G. Synthesis and biological activity of new 18β-glycyrrhetinic acid derivatives. Arab. J. Chem.,  2016, 9(3), 390-399.
 [http://dx.doi.org/10.1016/j.arabjc.2013.06.032]

[55]
Wang, R.; Zheng, Q.; Wang, W.; Feng, L.; Li, H.; Huai, Q. Design and synthesis of new anticancer glycyrrhetinic acids and oleanolic acids. Biol. Pharm. Bull.,  2017, 40(5), 703-710.
 [http://dx.doi.org/10.1248/bpb.b17-00016] [PMID: 28458357]

[56]
Emirdağ-Öztürk, S.; Karayıldırım, T.; Çapcı-Karagöz, A.; Alankuş-Çalışkan, Ö.; Özmen, A.; Poyrazoğlu-Çoban, E. Synthesis, antimicrobial and cytotoxic activities, and structure–activity relationships of gypsogenin derivatives against human cancer cells. Eur. J. Med. Chem.,  2014, 82, 565-573.
 [http://dx.doi.org/10.1016/j.ejmech.2014.05.084] [PMID: 24941130]

[57]
Ciftci, H.I.; Ozturk, S.E.; Ali, T.F.S.; Radwan, M.O.; Tateishi, H.; Koga, R.; Ocak, Z.; Can, M.; Otsuka, M.; Fujita, M. The first pentacyclic triterpenoid gypsogenin derivative exhibiting anti-ABL1 kinase and anti-chronic myelogenous leukemia activities. Biol. Pharm. Bull.,  2018, 41(4), 570-574.
 [http://dx.doi.org/10.1248/bpb.b17-00902] [PMID: 29386476]

[58]
Ciftci, H.I.; Radwan, M.O.; Ozturk, S.E.; Ulusoy, N.G.; Sozer, E.E.; Doha, E.O.; Zeynep, C.M. F.S, A.T.; Abd-Alla, H.I.; Yayli, N.T.; Hiroshi, O.; Masami, F. Design, synthesis and biological evaluation of pentacyclic triterpene derivatives: Optimization of anti-ABL kinase activity. Molecules,  2019, 24.
 [http://dx.doi.org/10.3390/molecules24193535]

[59]
Takeuchi, M.; Ashihara, E.; Yamazaki, Y.; Kimura, S.; Nakagawa, Y.; Tanaka, R.; Yao, H.; Nagao, R.; Hayashi, Y.; Hirai, H.; Maekawa, T. Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. Cancer Sci.,  2011, 102(3), 591-596.
 [http://dx.doi.org/10.1111/j.1349-7006.2010.01813.x] [PMID: 21166958]

[60]
Sang, F.; Ding, Y.; Wang, J.; Sun, B.; Sun, J.; Geng, Y.; Zhang, Z.; Ding, K.; Wu, L.L.; Liu, J.W.; Bai, C.; Yang, G.; Zhang, Q.; Li, L.Y.; Chen, Y. Structure-activity relationship study of rakicidins: Overcoming chronic myeloid leukemia resistance to imatinib with 4-methylester-rakicidin A. J. Med. Chem.,  2016, 59(3), 1184-1196.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b01841] [PMID: 26814890]

[61]
Hoelbl, A.; Schuster, C.; Kovacic, B.; Zhu, B.; Wickre, M.; Hoelzl, M.A.; Fajmann, S.; Grebien, F.; Warsch, W.; Stengl, G.; Hennighausen, L.; Poli, V.; Beug, H.; Moriggl, R.; Sexl, V. Stat5 is indispensable for the maintenance of bcr/abl ‐positive leukaemia. EMBO Mol. Med.,  2010, 2(3), 98-110.
 [http://dx.doi.org/10.1002/emmm.201000062] [PMID: 20201032]

[62]
Kato, Y.; Iwama, A.; Tadokoro, Y.; Shimoda, K.; Minoguchi, M.; Akira, S.; Tanaka, M.; Miyajima, A.; Kitamura, T.; Nakauchi, H. Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis. J. Exp. Med.,  2005, 202(1), 169-179.
 [http://dx.doi.org/10.1084/jem.20042541] [PMID: 15998795]

[63]
Romagnoli, R.; Baraldi, P.G.; Prencipe, F.; Lopez-Cara, C.; Rondanin, R.; Simoni, D.; Hamel, E.; Grimaudo, S.; Pipitone, R.M.; Meli, M.; Tolomeo, M. Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation. Eur. J. Med. Chem.,  2016, 108, 39-52.
 [http://dx.doi.org/10.1016/j.ejmech.2015.11.022] [PMID: 26629859]

[64]
Schepers, H.; Wierenga, A.T.J.; Vellenga, E.; Schuringa, J.J. STAT5-mediated self-renewal of normal hematopoietic and leukemic stem cells. JAK-STAT,  2012, 1(1), 13-25.
 [http://dx.doi.org/10.4161/jkst.19316] [PMID: 24058747]

[65]
Nelson, E.A.; Walker, S.R.; Xiang, M.; Weisberg, E.; Bar-Natan, M.; Barrett, R.; Liu, S.; Kharbanda, S.; Christie, A.L.; Nicolais, M.; Griffin, J.D.; Stone, R.M.; Kung, A.L.; Frank, D.A. The STAT5 inhibitor pimozide displays efficacy in models of acute myelogenous leukemia driven by FLT3 mutations. Genes Cancer,  2012, 3(7-8), 503-511.
 [http://dx.doi.org/10.1177/1947601912466555] [PMID: 23264850]

[66]
Bar-Natan, M.; Nelson, E.A.; Walker, S.R.; Kuang, Y.; Distel, R.J.; Frank, D.A. Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells. Leukemia,  2012, 26(6), 1407-1410.
 [http://dx.doi.org/10.1038/leu.2011.338] [PMID: 22134716]

[67]
Nelson, E.A.; Walker, S.R.; Weisberg, E.; Bar-Natan, M.; Barrett, R.; Gashin, L.B.; Terrell, S.; Klitgaard, J.L.; Santo, L.; Addorio, M.R.; Ebert, B.L.; Griffin, J.D.; Frank, D.A. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood,  2011, 117(12), 3421-3429.
 [http://dx.doi.org/10.1182/blood-2009-11-255232] [PMID: 21233313]

[68]
Rondanin, R.; Simoni, D.; Maccesi, M.; Romagnoli, R.; Grimaudo, S.; Pipitone, R.M.; Meli, M.; Cascio, A.; Tolomeo, M. Effects of pimozide derivatives on pSTAT5 in K562 cells. ChemMedChem,  2017, 12(15), 1183-1190.
 [http://dx.doi.org/10.1002/cmdc.201700234] [PMID: 28657677]

[69]
Crumb, W.J., Jr; Ekins, S.; Sarazan, R.D.; Wikel, J.H.; Wrighton, S.A.; Carlson, C.; Beasley, C.M., Jr Effects of antipsychotic drugs on I(to), I (Na), I (sus), I (K1), and hERG: QT prolongation, structure activity relationship, and network analysis. Pharm. Res.,  2006, 23(6), 1133-1143.
 [http://dx.doi.org/10.1007/s11095-006-0070-7] [PMID: 16715368]

[70]
Lien, J.C.; Huang, L.J.; Teng, C.M.; Wang, J.P.; Kuo, S.C. Synthesis of 2-alkoxy 1,4-naphthoquinone derivatives as antiplatelet, antiinflammatory, and antiallergic agents. Chem. Pharm. Bull.,  2002, 50(5), 672-674.
 [http://dx.doi.org/10.1248/cpb.50.672] [PMID: 12036028]

[71]
Jin, Y.R.; Ryu, C.K.; Moon, C.K.; Cho, M.R.; Yun, Y.P. Inhibitory effects of J78, a newly synthesized 1,4-naphthoquinone derivative, on experimental thrombosis and platelet aggregation. Pharmacology,  2004, 70(4), 195-200.
 [http://dx.doi.org/10.1159/000075548] [PMID: 15001820]

[72]
Ravichandiran, P.; Masłyk, M.; Sheet, S.; Janeczko, M.; Premnath, D.; Kim, A.R.; Park, B.H.; Han, M.K.; Yoo, D.J. Synthesis and antimicrobial evaluation of 1,4-naphthoquinone derivatives as potential antibacterial agents. ChemistryOpen,  2019, 8(5), 589-600.
 [http://dx.doi.org/10.1002/open.201900077] [PMID: 31098338]

[73]
Ravichandiran, P.; Subramaniyan, S.A.; Kim, S.Y.; Kim, J.S.; Park, B.H.; Shim, K.S.; Yoo, D.J. Synthesis and anticancer evaluation of 1,4-naphthoquinone derivatives containing a phenylaminosulfanyl moiety. ChemMedChem,  2019, 14(5), 532-544.
 [http://dx.doi.org/10.1002/cmdc.201800749] [PMID: 30600915]

[74]
Attoub, S.; Sperandio, O.; Raza, H.; Arafat, K.; Al-Salam, S.; Al Sultan, M.A.; Al Safi, M.; Takahashi, T.; Adem, A. Thymoquinone as an anticancer agent: Evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo. Fundam. Clin. Pharmacol.,  2013, 27(5), 557-569.
 [http://dx.doi.org/10.1111/j.1472-8206.2012.01056.x] [PMID: 22788741]

[75]
da Silva, E.N., Jr; Cavalcanti, B.C.; Guimarães, T.T.; Pinto, M.C.F.R.; Cabral, I.O.; Pessoa, C.; Costa-Lotufo, L.V.; de Moraes, M.O.; de Andrade, C.K.Z.; dos Santos, M.R.; de Simone, C.A.; Goulart, M.O.F.; Pinto, A.V. Synthesis and evaluation of quinonoid compounds against tumor cell lines. Eur. J. Med. Chem.,  2011, 46(1), 399-410.
 [http://dx.doi.org/10.1016/j.ejmech.2010.11.006] [PMID: 21115213]

[76]
Wellington, K.W.; Kolesnikova, N.I.; Nyoka, N.B.P.; McGaw, L.J. Investigation of the antimicrobial and anticancer activity of aminonaphthoquinones. Drug Dev. Res.,  2019, 80(1), 138-146.
 [http://dx.doi.org/10.1002/ddr.21477] [PMID: 30284739]

[77]
Chehl, N.; Chipitsyna, G.; Gong, Q.; Yeo, C.J.; Arafat, H.A. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford),  2009, 11(5), 373-381.
 [http://dx.doi.org/10.1111/j.1477-2574.2009.00059.x] [PMID: 19768141]

[78]
Mansour, M.A.; Nagi, M.N.; El-Khatib, A.S.; Al-Bekairi, A.M. Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: A possible mechanism of action. Cell Biochem. Funct.,  2002, 20(2), 143-151.
 [http://dx.doi.org/10.1002/cbf.968] [PMID: 11979510]

[79]
Bayrak, N.; Yıldırım, H.; Yıldız, M.; Radwan, M.O.; Otsuka, M.; Fujita, M.; Ciftci, H.I.; Tuyun, A.F. A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity. Chem. Biol. Drug Des.,  2020, 95(3), 343-354.
 [http://dx.doi.org/10.1111/cbdd.13651] [PMID: 31785034]

[80]
Bayrak, N.; Yıldırım, H.; Yıldız, M.; Radwan, M.O.; Otsuka, M.; Fujita, M.; Tuyun, A.F.; Ciftci, H.I. Design, synthesis, and biological activity of Plastoquinone analogs as a new class of anticancer agents. Bioorg. Chem.,  2019, 92, 103255.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103255] [PMID: 31542717]

[81]
Ciftci, H.I.; Bayrak, N.; Yıldız, M.; Yıldırım, H.; Sever, B.; Tateishi, H.; Otsuka, M.; Fujita, M.; Tuyun, A.F. Design, synthesis and investigation of the mechanism of action underlying anti-leukemic effects of the quinolinequinones as LY83583 analogs. Bioorg. Chem.,  2021, 114, 105160.
 [http://dx.doi.org/10.1016/j.bioorg.2021.105160] [PMID: 34328861]

[82]
Bayrak, N.; Ciftci, H.I.; Yıldız, M.; Yıldırım, H.; Sever, B.; Tateishi, H.; Otsuka, M.; Fujita, M.; Tuyun, A.F. Structure based design, synthesis, and evaluation of anti-CML activity of the quinolinequinones as LY83583 analogs. Chem. Biol. Interact.,  2021, 345, 109555.
 [http://dx.doi.org/10.1016/j.cbi.2021.109555] [PMID: 34146539]

[83]
Ciftci, H.I.; Bayrak, N.; Yıldırım, H.; Yıldız, M.; Radwan, M.O.; Otsuka, M.; Fujita, M.; Tuyun, A.F. Discovery and structure–activity relationship of plastoquinone analogs as anticancer agents against chronic myelogenous leukemia cells. Arch. Pharm.,  2019, 352(12), 1900170.
 [http://dx.doi.org/10.1002/ardp.201900170] [PMID: 31602720]

[84]
Desogus, A.; Schenone, S.; Brullo, C.; Tintori, C.; Musumeci, F. Bcr-Abl tyrosine kinase inhibitors: A patent review. Expert Opin. Ther. Pat.,  2015, 25(4), 397-412.
 [http://dx.doi.org/10.1517/13543776.2015.1012155] [PMID: 25656651]

[85]
Sharma, S.; Singh, J.; Ojha, R.; Singh, H.; Kaur, M.; Bedi, P.M.S.; Nepali, K. Design strategies, structure activity relationship and mechanistic insights for purines as kinase inhibitors. Eur. J. Med. Chem.,  2016, 112, 298-346.
 [http://dx.doi.org/10.1016/j.ejmech.2016.02.018] [PMID: 26907156]

[86]
Brasca, M.G.; Amboldi, N.; Ballinari, D.; Cameron, A.; Casale, E.; Cervi, G.; Colombo, M.; Colotta, F.; Croci, V.; D’Alessio, R.; Fiorentini, F.; Isacchi, A.; Mercurio, C.; Moretti, W.; Panzeri, A.; Pastori, W.; Pevarello, P.; Quartieri, F.; Roletto, F.; Traquandi, G.; Vianello, P.; Vulpetti, A.; Ciomei, M. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J. Med. Chem.,  2009, 52, 5152-5163.
 [http://dx.doi.org/10.1021/jm9006559] [PMID: 19603809]

[87]
Bertrand, J.; Dostálová, H.; Krystof, V.; Jorda, R.; Castro, A.; Mella, J.; Espinosa-Bustos, C.; María Zarate, A.; Salas, C.O. New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia. Bioorg. Chem.,  2020, 94, 103361.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103361] [PMID: 31699386]

[88]
Jabbour, E.; Morris, V.; Kantarjian, H.; Yin, C.C.; Burton, E.; Cortes, J. Characteristics and outcomes of patients with V299L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood,  2012, 120(16), 3382-3383.
 [http://dx.doi.org/10.1182/blood-2012-04-424192] [PMID: 23086624]

[89]
Wu, J.; Wang, A.; Li, X.; Chen, C.; Qi, Z.; Hu, C.; Wang, W.; Wu, H.; Huang, T.; Zhao, M.; Wang, W.; Hu, Z.; Liu, Q.; Wang, B.; Wang, L.; Li, L.; Ge, J.; Ren, T.; Xia, R.; Liu, J.; Liu, Q. Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML). Cancer Biol. Ther.,  2019, 20(6), 877-885.
 [http://dx.doi.org/10.1080/15384047.2019.1579958] [PMID: 30894066]

[90]
Zhou, Z.; Wang, Y.; Li, J.; Hu, B.; Lin, X.; Chen, Y.; Wang, R.; Liu, J.; Liu, H. Design, synthesis, and biological evaluation of Cyclobentinib (CB1107) as a potential anti-CML agent. Med. Chem. Res.,  2018, 27(8), 1863-1875.
 [http://dx.doi.org/10.1007/s00044-018-2198-5]

[91]
Zhao, X.; Zhang, J.; Liang, Y.; Li, J.; Ding, S.; Wang, Y.; Chen, Y.; Liu, J. Pharmacokinetics study of potential anti-CML drug Cyclobentinib (CB1107) by HPLC–MS/MS. J. Pharmaceu. Bioph. Rese.,  2021, 3(1), 169-175.
 [http://dx.doi.org/10.25082/JPBR.2021.01.001]

[92]
Chapman, T.M.; Bouloc, N.; Buxton, R.S.; Chugh, J.; Lougheed, K.E.A.; Osborne, S.A.; Saxty, B.; Smerdon, S.J.; Taylor, D.L.; Whalley, D. Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis. Bioorg. Med. Chem. Lett.,  2012, 22(9), 3349-3353.
 [http://dx.doi.org/10.1016/j.bmcl.2012.02.107] [PMID: 22469702]

[93]
Kamenecka, T.; Jiang, R.; Song, X.; Duckett, D.; Chen, W.; Ling, Y.Y.; Habel, J.; Laughlin, J.D.; Chambers, J.; Figuera-Losada, M.; Cameron, M.D.; Lin, L.; Ruiz, C.H.; LoGrasso, P.V. Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J. Med. Chem.,  2010, 53(1), 419-431.
 [http://dx.doi.org/10.1021/jm901351f] [PMID: 19947601]

[94]
Kim, S.; Jung, J.K.; Lee, H.S.; Kim, Y.; Kim, J.; Choi, K.; Baek, D.J.; Moon, B.; Oh, K.S.; Lee, B.H.; Shin, K.J.; Pae, A.N.; Nam, G.; Roh, E.J.; Cho, Y.S.; Choo, H. Discovery of piperidinyl aminopyrimidine derivatives as IKK-2 inhibitors. Bioorg. Med. Chem. Lett.,  2011, 21(10), 3002-3006.
 [http://dx.doi.org/10.1016/j.bmcl.2011.03.044] [PMID: 21489792]

[95]
Choi, H.G.; Ren, P.; Adrian, F.; Sun, F.; Lee, H.S.; Wang, X.; Ding, Q.; Zhang, G.; Xie, Y.; Zhang, J.; Liu, Y.; Tuntland, T.; Warmuth, M.; Manley, P.W.; Mestan, J.; Gray, N.S.; Sim, T. A type-II kinase inhibitor capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl. J. Med. Chem.,  2010, 53(15), 5439-5448.
 [http://dx.doi.org/10.1021/jm901808w] [PMID: 20604564]

[96]
Liang, X.; Liu, X.; Wang, B.; Zou, F.; Wang, A.; Qi, S.; Chen, C.; Zhao, Z.; Wang, W.; Qi, Z.; Lv, F.; Hu, Z.; Wang, L.; Zhang, S.; Liu, Q.; Liu, J. Discovery of 2-((3-Amino-4-methylphenyl)amino)- N -(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053) as a Potent, Selective, and Orally Available BCR-ABL/SRC/p38 Kinase In-hibitor for Chronic Myeloid Leukemia. J. Med. Chem.,  2016, 59(5), 1984-2004.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b01618] [PMID: 26789553]

[97]
Liang, H.; Zou, F.; Liu, Q.; Wang, B.; Fu, L.; Liang, X.; Liu, J.; Liu, Q. Nanocrystal-loaded liposome for targeted delivery of poorly water-soluble antitumor drugs with high drug loading and stability towards efficient cancer therapy. Int. J. Pharm.,  2021, 599, 120418.
 [http://dx.doi.org/10.1016/j.ijpharm.2021.120418] [PMID: 33647414]

[98]
Liu, F.; Wang, B.; Wang, Q.; Qi, Z.; Chen, C.; Kong, L.L.; Chen, J.Y.; Liu, X.; Wang, A.; Hu, C.; Wang, W.; Wang, H.; Wu, F.; Ruan, Y.; Qi, S.; Liu, J.; Zou, F.; Hu, Z.; Wang, W.; Wang, L.; Zhang, S.; Yun, C.H.; Zhai, Z.; Liu, J.; Liu, Q. Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML). Oncotarget,  2016, 7(29), 45562-45574.
 [http://dx.doi.org/10.18632/oncotarget.10037] [PMID: 27322145]

[99]
Wang, Q.; Liu, F.; Wang, B.; Zou, F.; Qi, Z.; Chen, C.; Yu, K.; Hu, C.; Qi, S.; Wang, W.; Hu, Z.; Liu, J.; Wang, W.; Wang, L.; Liang, Q.; Zhang, S.; Ren, T.; Liu, Q.; Liu, J. Discovery of 4-Methyl- N -(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-nicotinoylpiperidin-4-yl)oxy)benzamide (CHMFL-ABL/KIT-155) as a Novel Highly Potent Type II ABL/KIT Dual Kinase Inhibitor with a Distinct Hinge Binding. J. Med. Chem.,  2017, 60(1), 273-289.
 [http://dx.doi.org/10.1021/acs.jmedchem.6b01290] [PMID: 27966954]

[100]
Rini, B.I.; Escudier, B.; Tomczak, P.; Kaprin, A.; Szczylik, C.; Hutson, T.E.; Michaelson, M.D.; Gorbunova, V.A.; Gore, M.E.; Rusakov, I.G.; Negrier, S.; Ou, Y.C.; Castellano, D.; Lim, H.Y.; Uemura, H.; Tarazi, J.; Cella, D.; Chen, C.; Rosbrook, B.; Kim, S.; Motzer, R.J. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet,  2011, 378(9807), 1931-1939.
 [http://dx.doi.org/10.1016/S0140-6736(11)61613-9] [PMID: 22056247]

[101]
Pemovska, T.; Johnson, E.; Kontro, M.; Repasky, G.A.; Chen, J.; Wells, P.; Cronin, C.N.; McTigue, M.; Kallioniemi, O.; Porkka, K.; Murray, B.W.; Wennerberg, K. Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. Nature,  2015, 519(7541), 102-105.
 [http://dx.doi.org/10.1038/nature14119] [PMID: 25686603]

[102]
Liu, X.; Wang, B.; Chen, C.; Jiang, Z.; Hu, C.; Wu, H.; Zhang, Y.; Liu, X.; Wang, W.; Wang, J.; Hu, Z.; Wang, A.; Huang, T.; Liu, Q.; Wang, W.; Wang, L.; Wang, W.; Ren, T.; Li, L.; Xia, R.; Ge, J.; Liu, Q.; Liu, J. Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia. Eur. J. Med. Chem.,  2018, 160, 61-81.
 [http://dx.doi.org/10.1016/j.ejmech.2018.10.007] [PMID: 30317026]

[103]
Luo, Y.; Jiang, F.; Cole, T.B.; Hradil, V.P.; Reuter, D.; Chakravartty, A.; Albert, D.H.; Davidsen, S.K.; Cox, B.F.; McKeegan, E.M.; Fox, G.B. A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model. Cancer Chemother. Pharmacol.,  2012, 69(4), 911-921.
 [http://dx.doi.org/10.1007/s00280-011-1740-7] [PMID: 22080168]

[104]
Shan, Y.; Dong, J.; Pan, X.; Zhang, L.; Zhang, J.; Dong, Y.; Wang, M. Expanding the structural diversity of Bcr-Abl inhibitors: Dibenzoylpiperazin incorporated with 1H-indazol-3-amine. Eur. J. Med. Chem.,  2015, 104, 139-147.
 [http://dx.doi.org/10.1016/j.ejmech.2015.09.034] [PMID: 26451772]

[105]
Pan, X.; Dong, J.; Shi, Y.; Shao, R.; Wei, F.; Wang, J.; Zhang, J. Discovery of novel Bcr-Abl inhibitors with diacylated piperazine as the flexible linker. Org. Biomol. Chem.,  2015, 13(25), 7050-7066.
 [http://dx.doi.org/10.1039/C5OB00430F] [PMID: 26052668]

[106]
Pan, X.; Liang, L.; Sun, Y.; Si, R.; Zhang, Q.; Wang, J.; Fu, J.; Zhang, J.; Zhang, J. Discovery of novel Bcr-AblT315I inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety. Eur. J. Med. Chem.,  2019, 178, 232-242.
 [http://dx.doi.org/10.1016/j.ejmech.2019.05.091] [PMID: 31185413]

[107]
Pan, X.; Liu, N.; Zhang, Q.; Wang, K.; Li, Y.; Shan, Y.; Li, Z.; Zhang, J. Design, synthesis, and biological evaluation of novel Bcr-AblT315I inhibitors incorporating amino acids as flexible linker. Bioorg. Med. Chem.,  2021, 48, 116398.
 [http://dx.doi.org/10.1016/j.bmc.2021.116398] [PMID: 34547714]

[108]
Aghel, N.; Delgado, D.H.; Lipton, J.H. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: Preventive strategies and cardiovascular surveillance. Vasc. Health Risk Manag.,  2017, 13, 293-303.
 [http://dx.doi.org/10.2147/VHRM.S108874] [PMID: 28831263]

[109]
Moslehi, J.J.; Deininger, M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J. Clin. Oncol.,  2015, 33(35), 4210-4218.
 [http://dx.doi.org/10.1200/JCO.2015.62.4718] [PMID: 26371140]

[110]
Gibbons, D.L.; Pricl, S.; Kantarjian, H.; Cortes, J.; Quintás-Cardama, A. The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm. Cancer,  2012, 118(2), 293-299.
 [http://dx.doi.org/10.1002/cncr.26225] [PMID: 21732333]

[111]
Larocque, E.; Chu, E.F.Y.; Naganna, N.; Sintim, H.O. Nicotinamide-ponatinib analogues as potent anti-CML and Anti-AML compounds. ACS Omega,  2020, 5(6), 2690-2698.
 [http://dx.doi.org/10.1021/acsomega.9b03223] [PMID: 32095692]

[112]
Sun, Y.; Zhao, N.; Wang, H.; Wu, Q.; Han, Y.; Liu, Q.; Wu, M.; Liu, Y.; Kong, F.; Wang, H.; Sun, Y.; Sun, D.; Jing, L.; Tang, G.; Hu, Y.; Xiao, D.; Luo, H.; Han, Y.; Peng, Y. CT-721, a potent Bcr-Abl inhibitor, exhibits excellent in vitro and in vivo efficacy in the treatment of chronic myeloid leukemia. J. Cancer,  2017, 8(14), 2774-2784.
 [http://dx.doi.org/10.7150/jca.18731] [PMID: 28928866]

[113]
Lu, X.; Zhang, Z.; Ren, X.; Wang, D.; Ding, K. Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl T315I inhibitor overcoming acquired imatinib resistance. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 331-336.
 [http://dx.doi.org/10.1080/14756366.2016.1250757] [PMID: 28260399]

[114]
El-Damasy, A.K.; Jin, H.; Seo, S.H.; Bang, E.K.; Keum, G. Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity. Eur. J. Med. Chem.,  2020, 207, 112710.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112710] [PMID: 32961435]

[115]
Ren, X.; Pan, X.; Zhang, Z.; Wang, D.; Lu, X.; Li, Y.; Wen, D.; Long, H.; Luo, J.; Feng, Y.; Zhuang, X.; Zhang, F.; Liu, J.; Leng, F.; Lang, X.; Bai, Y.; She, M.; Tu, Z.; Pan, J.; Ding, K. Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J. Med. Chem.,  2013, 56(3), 879-894.
 [http://dx.doi.org/10.1021/jm301581y] [PMID: 23301703]

[116]
Liu, X.; Wang, G.; Yan, X.; Qiu, H.; Min, P.; Wu, M.; Tang, C.; Zhang, F.; Tang, Q.; Zhu, S.; Qiu, M.; Zhuang, W.; Fang, D.D.; Zhou, Z.; Yang, D.; Zhai, Y. Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors. Cell Biosci.,  2019, 9(1), 88.
 [http://dx.doi.org/10.1186/s13578-019-0351-6] [PMID: 31673329]

[117]
Wang, Y.; Zhang, L.; Tang, X.; Luo, J.; Tu, Z.; Jiang, K.; Ren, X.; Xu, F.; Chan, S.; Li, Y.; Zhang, Z.; Ding, K. GZD824 as a FLT3, FGFR1 and PDGFRα inhibitor against leukemia in vitro and in vivo. Transl. Oncol.,  2020, 13(4), 100766.
 [http://dx.doi.org/10.1016/j.tranon.2020.100766] [PMID: 32247263]

[118]
 National medical products administration. specialized information services: China drug administration approved the marketing of olverembatinib tablets with conditions. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process [Accessed on: Jan 2, 2022].

[119]
Nagar, B.; Bornmann, W.G.; Pellicena, P.; Schindler, T.; Veach, D.R.; Miller, W.T.; Clarkson, B.; Kuriyan, J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res.,  2002, 62(15), 4236-4243.
 [PMID: 12154025]

[120]
Tokarski, J.S.; Newitt, J.A.; Chang, C.Y.J.; Cheng, J.D.; Wittekind, M.; Kiefer, S.E.; Kish, K.; Lee, F.Y.F.; Borzillerri, R.; Lombardo, L.J.; Xie, D.; Zhang, Y.; Klei, H.E. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res.,  2006, 66(11), 5790-5797.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-4187] [PMID: 16740718]

[121]
Liu, J.; Huang, H.; Deng, X.; Xiong, R.; Cao, X.; Tang, G.; Wu, X.; Xu, S.; Peng, J. Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide–benzamide derivatives. RSC Advances,  2019, 9(4), 2092-2101.
 [http://dx.doi.org/10.1039/C8RA10096A] [PMID: 35516138]

[122]
Zhang, Y.; Liu, J.; Wu, X.; Yang, S.; Li, Y.; Liu, S.; Zhu, S.; Cao, X.; Xie, Z.; Lei, X.; Huang, H.; Peng, J. Anti-chronic myeloid leukemia activity and quantitative structure-activity relationship of novel thiazole aminobenzamide derivatives. Bioorg. Med. Chem. Lett.,  2021, 44, 128116.
 [http://dx.doi.org/10.1016/j.bmcl.2021.128116] [PMID: 34015503]

[123]
Lu, T.; Cao, J.; Zou, F.; Li, X.; Wang, A.; Wang, W.; Liang, H.; Liu, Q.; Hu, C.; Chen, C.; Hu, Z.; Wang, W.; Li, L.; Ge, J.; Shen, Y.; Ren, T.; Liu, J.; Xia, R.; Liu, Q. Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML). Eur. J. Pharmacol.,  2021, 897, 173944.
 [http://dx.doi.org/10.1016/j.ejphar.2021.173944] [PMID: 33581133]

[124]
El-Moghazy, S.M.; George, R.F.; Osman, E.E.A.; Elbatrawy, A.A.; Kissova, M.; Colombo, A.; Crespan, E.; Maga, G. Novel pyrazolo[3,4- d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line. Eur. J. Med. Chem.,  2016, 123, 1-13.
 [http://dx.doi.org/10.1016/j.ejmech.2016.07.034] [PMID: 27474918]

[125]
Schoepfer, J.; Jahnke, W.; Berellini, G.; Buonamici, S.; Cotesta, S.; Cowan-Jacob, S.W.; Dodd, S.; Drueckes, P.; Fabbro, D.; Gabriel, T.; Groell, J.M.; Grotzfeld, R.M.; Hassan, A.Q.; Henry, C.; Iyer, V.; Jones, D.; Lombardo, F.; Loo, A.; Manley, P.W.; Pellé, X.; Rummel, G.; Salem, B.; Warmuth, M.; Wylie, A.A.; Zoller, T.; Marzinzik, A.L.; Furet, P. Discovery of Asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J. Med. Chem.,  2018, 61(18), 8120-8135.
 [http://dx.doi.org/10.1021/acs.jmedchem.8b01040] [PMID: 30137981]

[126]
Wylie, A.A.; Schoepfer, J.; Jahnke, W.; Cowan-Jacob, S.W.; Loo, A.; Furet, P.; Marzinzik, A.L.; Pelle, X.; Donovan, J.; Zhu, W.; Buonamici, S.; Hassan, A.Q.; Lombardo, F.; Iyer, V.; Palmer, M.; Berellini, G.; Dodd, S.; Thohan, S.; Bitter, H.; Branford, S.; Ross, D.M.; Hughes, T.P.; Petruzzelli, L.; Vanasse, K.G.; Warmuth, M.; Hofmann, F.; Keen, N.J.; Sellers, W.R. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature,  2017, 543(7647), 733-737.
 [http://dx.doi.org/10.1038/nature21702] [PMID: 28329763]

[127]
Hughes, T.P.; Mauro, M.J.; Cortes, J.E.; Minami, H.; Rea, D.; DeAngelo, D.J.; Breccia, M.; Goh, Y.T.; Talpaz, M.; Hochhaus, A.; le Coutre, P.; Ottmann, O.; Heinrich, M.C.; Steegmann, J.L.; Deininger, M.W.N.; Janssen, J.J.W.M.; Mahon, F.X.; Minami, Y.; Yeung, D.; Ross, D.M.; Tallman, M.S.; Park, J.H.; Druker, B.J.; Hynds, D.; Duan, Y.; Meille, C.; Hourcade-Potelleret, F.; Vanasse, K.G.; Lang, F.; Kim, D.W. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N. Engl. J. Med.,  2019, 381(24), 2315-2326.
 [http://dx.doi.org/10.1056/NEJMoa1902328] [PMID: 31826340]

[128]
 U.S. Food & drug administration. drug databases: Drugs@FDA: FDA-approved drugs. Available From: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process [Accessed on: Jan 2, 2022].

[129]
Zhao, Q.; Ren, C.; Liu, L.; Chen, J.; Shao, Y.; Sun, N.; Sun, R.; Kong, Y.; Ding, X.; Zhang, X.; Xu, Y.; Yang, B.; Yin, Q.; Yang, X.; Jiang, B. Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting Von Hippel-Lindau (VHL) E3 ubiquitin ligase. J. Med. Chem.,  2019, 62(20), 9281-9298.
 [http://dx.doi.org/10.1021/acs.jmedchem.9b01264] [PMID: 31539241]

[130]
Deng, X.; Okram, B.; Ding, Q.; Zhang, J.; Choi, Y.; Adrián, F.J.; Wojciechowski, A.; Zhang, G.; Che, J.; Bursulaya, B.; Cowan-Jacob, S.W.; Rummel, G.; Sim, T.; Gray, N.S. Expanding the diversity of allosteric bcr-abl inhibitors. J. Med. Chem.,  2010, 53(19), 6934-6946.
 [http://dx.doi.org/10.1021/jm100555f] [PMID: 20828158]

[131]
Burslem, G.M.; Schultz, A.R.; Bondeson, D.P.; Eide, C.A.; Savage Stevens, S.L.; Druker, B.J.; Crews, C.M. Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation. Cancer Res.,  2019, 79(18), 4744-4753.
 [http://dx.doi.org/10.1158/0008-5472.CAN-19-1236] [PMID: 31311809]

[132]
Shimokawa, K.; Shibata, N.; Sameshima, T.; Miyamoto, N.; Ujikawa, O.; Nara, H.; Ohoka, N.; Hattori, T.; Cho, N.; Naito, M. Targeting the allosteric site of oncoprotein BCR-ABL as an alternative strategy for effective target protein degradation. ACS Med. Chem. Lett.,  2017, 8(10), 1042-1047.
 [http://dx.doi.org/10.1021/acsmedchemlett.7b00247] [PMID: 29057048]

[133]
Demizu, Y.; Shibata, N.; Hattori, T.; Ohoka, N.; Motoi, H.; Misawa, T.; Shoda, T.; Naito, M.; Kurihara, M. Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. Bioorg. Med. Chem. Lett.,  2016, 26(20), 4865-4869.
 [http://dx.doi.org/10.1016/j.bmcl.2016.09.041] [PMID: 27666635]

[134]
Shibata, N.; Miyamoto, N.; Nagai, K.; Shimokawa, K.; Sameshima, T.; Ohoka, N.; Hattori, T.; Imaeda, Y.; Nara, H.; Cho, N.; Naito, M. Development of protein degradation inducers of oncogenic BCR ‐ ABL protein by conjugation of ABL kinase inhibitors and IAP ligands. Cancer Sci.,  2017, 108(8), 1657-1666.
 [http://dx.doi.org/10.1111/cas.13284] [PMID: 28556300]

[135]
Liu, H.; Ding, X.; Liu, L.; Mi, Q.; Zhao, Q.; Shao, Y.; Ren, C.; Chen, J.; Kong, Y.; Qiu, X.; Elvassore, N.; Yang, X.; Yin, Q.; Jiang, B. Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation. Eur. J. Med. Chem.,  2021, 223, 113645.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113645] [PMID: 34217059]
Cite As
Mini-Reviews in Medicinal Chemistry

The Progress of Small Molecule Targeting BCR-ABL in the Treatment of Chronic Myeloid Leukemia

Abstract

Graphical Abstract
