Current Medicinal Insights on Synthetic Small Molecules and Natural Origin Products as PD-1/PD-L1 Inhibitors

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Abstract

Cancer is one of the leading causes of death worldwide. Each year, millions of people are diagnosed with cancer; hence, researchers have always been curious and busy developing cancer treatments. Despite thousands of studies, cancer is still a major threat to human beings. One of the mechanisms through which cancer invades a human being is the immune escape mechanism, which has been the focus of studies in the past years. PD-1/PD-L1 pathway plays a major role in this immune escape. Therefore, research focusing on blocking this pathway has led to the discovery of molecules based on monoclonal antibodies that work quite well, but despite the successful application of monoclonal antibodies as inhibitors of the PD-1/PD-L1 pathway, there are some drawbacks, such as poor bioavailability and several immune-related adverse effects, which have led the researchers toward further investigation, thereby resulting in the discovery of different types of molecules, such as small molecule inhibitors, PROTAC-based molecules, and naturally derived peptide molecules that function as inhibitors of the PD-1/PD-L1 pathway. Here, in this review, we have summarized recent findings of these molecules and focused on their structural activity relationship. The development of these molecules has opened more prospects in cancer therapy.

Graphical Abstract

[1]
Fidler, M.M.; Bray, F.; Soerjomataram, I. The global cancer burden and human development: A review. Scand. J. Public Health, 2018, 46(1), 27-36.
[http://dx.doi.org/10.1177/1403494817715400] [PMID: 28669281]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin., 2016, 66(1), 7-30.
[http://dx.doi.org/10.3322/caac.21332] [PMID: 26742998]
[3]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[4]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[5]
Konstantinidou, M.; Zarganes-Tzitzikas, T.; Magiera-Mularz, K.; Holak, T.A.; Dömling, A. Immune checkpoint PD-1/PD-L1: Is there life beyond antibodies? Angew. Chem. Int. Ed., 2018, 57(18), 4840-4848.
[http://dx.doi.org/10.1002/anie.201710407] [PMID: 29178534]
[6]
Dömling, A.; Holak, T.A. Programmed death-1: Therapeutic success after more than 100 years of cancer immunotherapy. Angew. Chem. Int. Ed., 2014, 53(9), 2286-2288.
[http://dx.doi.org/10.1002/anie.201307906] [PMID: 24474145]
[7]
Gotwals, P.; Cameron, S.; Cipolletta, D.; Cremasco, V.; Crystal, A.; Hewes, B.; Mueller, B.; Quaratino, S.; Sabatos-Peyton, C.; Petruzzelli, L.; Engelman, J.A.; Dranoff, G. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer, 2017, 17(5), 286-301.
[http://dx.doi.org/10.1038/nrc.2017.17] [PMID: 28338065]
[8]
Yang, Y. Cancer immunotherapy: Harnessing the immune system to battle cancer. J. Clin. Invest., 2015, 125(9), 3335-3337.
[http://dx.doi.org/10.1172/JCI83871] [PMID: 26325031]
[9]
Freeman, G.J.; Long, A.J.; Iwai, Y.; Bourque, K.; Chernova, T.; Nishimura, H.; Fitz, L.J.; Malenkovich, N.; Okazaki, T.; Byrne, M.C.; Horton, H.F.; Fouser, L.; Carter, L.; Ling, V.; Bowman, M.R.; Carreno, B.M.; Collins, M.; Wood, C.R.; Honjo, T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med., 2000, 192(7), 1027-1034.
[http://dx.doi.org/10.1084/jem.192.7.1027] [PMID: 11015443]
[10]
Dong, H.; Zhu, G.; Tamada, K.; Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med., 1999, 5(12), 1365-1369.
[http://dx.doi.org/10.1038/70932] [PMID: 10581077]
[11]
Chen, L.; Han, X. Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest., 2015, 125(9), 3384-3391.
[http://dx.doi.org/10.1172/JCI80011] [PMID: 26325035]
[12]
Qin, W.; Hu, L.; Zhang, X.; Jiang, S.; Li, J.; Zhang, Z.; Wang, X. The diverse function of PD-1/PD-L pathway beyond cancer. Front. Immunol., 2019, 10, 2298.
[http://dx.doi.org/10.3389/fimmu.2019.02298] [PMID: 31636634]
[13]
Sharma, P.; Allison, J.P. Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell, 2015, 161(2), 205-214.
[http://dx.doi.org/10.1016/j.cell.2015.03.030] [PMID: 25860605]
[14]
Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer, 2016, 16(5), 275-287.
[http://dx.doi.org/10.1038/nrc.2016.36] [PMID: 27079802]
[15]
Zhulai, G.; Oleinik, E. Targeting regulatory T cells in anti‐PD‐1/PD‐L1 cancer immunotherapy. Scand. J. Immunol., 2022, 95(3), e13129.
[http://dx.doi.org/10.1111/sji.13129] [PMID: 34936125]
[16]
Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382), 1350-1355.
[http://dx.doi.org/10.1126/science.aar4060] [PMID: 29567705]
[17]
Ohaegbulam, K.C.; Assal, A.; Lazar-Molnar, E.; Yao, Y.; Zang, X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol. Med., 2015, 21(1), 24-33.
[http://dx.doi.org/10.1016/j.molmed.2014.10.009] [PMID: 25440090]
[18]
Harding, F.A.; Stickler, M.M.; Razo, J.; DuBridge, R. The immunogenicity of humanized and fully human antibodies. MAbs, 2010, 2(3), 256-265.
[http://dx.doi.org/10.4161/mabs.2.3.11641] [PMID: 20400861]
[19]
Nelson, A.L.; Dhimolea, E.; Reichert, J.M. Development trends for human monoclonal antibody therapeutics. Nat. Rev. Drug Discov., 2010, 9(10), 767-774.
[http://dx.doi.org/10.1038/nrd3229] [PMID: 20811384]
[20]
Naidoo, J.; Page, D.B.; Li, B.T.; Connell, L.C.; Schindler, K.; Lacouture, M.E.; Postow, M.A.; Wolchok, J.D. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann. Oncol., 2015, 26(12), 2375-2391.
[http://dx.doi.org/10.1093/annonc/mdv383] [PMID: 26371282]
[21]
Guzik, K.; Tomala, M.; Muszak, D.; Konieczny, M.; Hec, A.; Błaszkiewicz, U.; Pustuła, M.; Butera, R.; Dömling, A.; Holak, T.A. Development of the Inhibitors that target the PD-1/PD-L1 Interaction—A brief look at progress on small molecules, peptides and macrocycles. Molecules, 2019, 24(11), 2071.
[http://dx.doi.org/10.3390/molecules24112071] [PMID: 31151293]
[22]
Zak, K.M.; Grudnik, P.; Guzik, K.; Zieba, B.J.; Musielak, B.; Dömling, A.; Dubin, G.; Holak, T.A. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget, 2016, 7(21), 30323-30335.
[http://dx.doi.org/10.18632/oncotarget.8730] [PMID: 27083005]
[23]
Skalniak, L.; Zak, K.M.; Guzik, K.; Magiera, K.; Musielak, B.; Pachota, M.; Szelazek, B.; Kocik, J.; Grudnik, P.; Tomala, M.; Krzanik, S.; Pyrc, K.; Dömling, A.; Dubin, G.; Holak, T.A. Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells. Oncotarget, 2017, 8(42), 72167-72181.
[http://dx.doi.org/10.18632/oncotarget.20050] [PMID: 29069777]
[24]
Chupak, L.S.; Zheng, X. Compounds useful as immunomodulators., 2015.
[25]
Zak, K.M.; Kitel, R.; Przetocka, S.; Golik, P.; Guzik, K.; Musielak, B.; Dömling, A.; Dubin, G.; Holak, T.A. Structure of the complex of human programmed death 1, PD-1, and its ligand PD-L1. Structure, 2015, 23(12), 2341-2348.
[http://dx.doi.org/10.1016/j.str.2015.09.010] [PMID: 26602187]
[26]
OuYang, Y.; Gao, J.; Zhao, L.; Lu, J.; Zhong, H.; Tang, H.; Jin, S.; Yue, L.; Li, Y.; Guo, W.; Xu, Q.; Lai, Y. Design, synthesis, and evaluation of o -(Biphenyl-3-ylmethoxy)nitrophenyl derivatives as PD-1/PD-L1 inhibitors with potent anticancer efficacy In Vivo. J. Med. Chem., 2021, 64(11), 7646-7666.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00370] [PMID: 34037385]
[27]
Basu, S.; Yang, J.; Xu, B.; Magiera-Mularz, K.; Skalniak, L.; Musielak, B.; Kholodovych, V.; Holak, T.A.; Hu, L. Design, synthesis, evaluation, and structural studies of C2 -symmetric small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 protein–protein interaction. J. Med. Chem., 2019, 62(15), 7250-7263.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00795] [PMID: 31298541]
[28]
Guo, J.; Luo, L.; Wang, Z.; Hu, N.; Wang, W.; Xie, F.; Liang, E.; Yan, X.; Xiao, J.; Li, S. Design, synthesis, and biological evaluation of linear aliphatic amine-linked triaryl derivatives as potent small-molecule inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction with promising antitumor effects in vivo. J. Med. Chem., 2020, 63(22), 13825-13850.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01329] [PMID: 33186040]
[29]
Wang, Y.; Xu, Z.; Wu, T.; He, M.; Zhang, N. Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof. Patent WO/2018/006795, 2021.
[30]
Qin, M.; Cao, Q.; Zheng, S.; Tian, Y.; Zhang, H.; Xie, J.; Xie, H.; Liu, Y.; Zhao, Y.; Gong, P. Discovery of [1, 2, 4] triazolo [4, 3-a] pyridines as potent inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 interaction. J. Med. Chem., 2019, 62(9), 4703-4715.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00312] [PMID: 30964291]
[31]
Park, J.J.; Thi, E.P.; Carpio, V.H.; Bi, Y.; Cole, A.G.; Dorsey, B.D.; Fan, K.; Harasym, T.; Iott, C.L.; Kadhim, S.; Kim, J.H.; Lee, A.C.H.; Nguyen, D.; Paratala, B.S.; Qiu, R.; White, A.; Lakshminarasimhan, D.; Leo, C.; Suto, R.K.; Rijnbrand, R.; Tang, S.; Sofia, M.J.; Moore, C.B. Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1. Nat. Commun., 2021, 12(1), 1222.
[http://dx.doi.org/10.1038/s41467-021-21410-1] [PMID: 33619272]
[32]
Cheng, B.; Ren, Y.; Niu, X.; Wang, W.; Wang, S.; Tu, Y.; Liu, S.; Wang, J.; Yang, D.; Liao, G.; Chen, J. Discovery of novel resorcinol dibenzyl ethers targeting the programmed cell death-1/programmed cell death–ligand 1 interaction as potential anticancer agents. J. Med. Chem., 2020, 63(15), 8338-8358.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00574] [PMID: 32667799]
[33]
Cheng, B.; Wang, W.; Niu, X.; Ren, Y.; Liu, T.; Cao, H.; Wang, S.; Tu, Y.; Chen, J.; Liu, S.; Yang, X.; Chen, J. Discovery of novel and highly potent resorcinol dibenzyl ether-based PD-1/PD-L1 inhibitors with improved drug-like and pharmacokinetic properties for cancer treatment. J. Med. Chem., 2020, 63(24), 15946-15959.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01684] [PMID: 33264007]
[34]
Guzik, K.; Zak, K.M.; Grudnik, P.; Magiera, K.; Musielak, B.; Törner, R.; Skalniak, L.; Dömling, A.; Dubin, G.; Holak, T.A. Small-molecule inhibitors of the programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) interaction via transiently induced protein states and dimerization of PD-L1. J. Med. Chem., 2017, 60(13), 5857-5867.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00293] [PMID: 28613862]
[35]
Konieczny, M.; Musielak, B.; Kocik, J.; Skalniak, L.; Sala, D.; Czub, M.; Magiera-Mularz, K.; Rodriguez, I.; Myrcha, M.; Stec, M.; Siedlar, M.; Holak, T.A.; Plewka, J. Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint. J. Med. Chem., 2020, 63(19), 11271-11285.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01260] [PMID: 32936638]
[36]
Liu, L.; Yao, Z.; Wang, S.; Xie, T.; Wu, G.; Zhang, H.; Zhang, P.; Wu, Y.; Yuan, H.; Sun, H. Syntheses, biological evaluations, and mechanistic studies of benzo [c][1, 2, 5] oxadiazole derivatives as potent PD-L1 inhibitors with in vivo antitumor activity. J. Med. Chem., 2021, 64(12), 8391-8409.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00392] [PMID: 34115499]
[37]
Gong, J.; Chehrazi-Raffle, A.; Reddi, S.; Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. J. Immunother. Cancer, 2018, 6(1), 8.
[http://dx.doi.org/10.1186/s40425-018-0316-z] [PMID: 29357948]
[38]
Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 2012, 12(4), 252-264.
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
[39]
Mellman, I.; Coukos, G.; Dranoff, G. Cancer immunotherapy comes of age. Nature, 2011, 480(7378), 480-489.
[http://dx.doi.org/10.1038/nature10673] [PMID: 22193102]
[40]
Topalian, S.L.; Drake, C.G.; Pardoll, D.M. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell, 2015, 27(4), 450-461.
[http://dx.doi.org/10.1016/j.ccell.2015.03.001] [PMID: 25858804]
[41]
Yang, J.; Hu, L. Immunomodulators targeting the PD-1/PD-L1 protein-protein interaction: From antibodies to small molecules. Med. Res. Rev., 2019, 39(1), 265-301.
[http://dx.doi.org/10.1002/med.21530] [PMID: 30215856]
[42]
Cheng, X.; Veverka, V.; Radhakrishnan, A.; Waters, L.C.; Muskett, F.W.; Morgan, S.H.; Huo, J.; Yu, C.; Evans, E.J.; Leslie, A.J.; Griffiths, M.; Stubberfield, C.; Griffin, R.; Henry, A.J.; Jansson, A.; Ladbury, J.E.; Ikemizu, S.; Carr, M.D.; Davis, S.J. Structure and interactions of the human programmed cell death 1 receptor. J. Biol. Chem., 2013, 288(17), 11771-11785.
[http://dx.doi.org/10.1074/jbc.M112.448126] [PMID: 23417675]
[43]
Riella, L.V.; Paterson, A.M.; Sharpe, A.H.; Chandraker, A. Role of the PD-1 pathway in the immune response. Am. J. Transplant., 2012, 12(10), 2575-2587.
[http://dx.doi.org/10.1111/j.1600-6143.2012.04224.x] [PMID: 22900886]
[44]
Wherry, E.J. T cell exhaustion. Nat. Immunol., 2011, 12(6), 492-499.
[http://dx.doi.org/10.1038/ni.2035] [PMID: 21739672]
[45]
Taube, J.M.; Anders, R.A.; Young, G.D.; Xu, H.; Sharma, R.; McMiller, T.L.; Chen, S.; Klein, A.P.; Pardoll, D.M.; Topalian, S.L.; Chen, L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med., 2012, 4(127), 127ra37.
[http://dx.doi.org/10.1126/scitranslmed.3003689] [PMID: 22461641]
[46]
Francisco, L.M.; Salinas, V.H.; Brown, K.E.; Vanguri, V.K.; Freeman, G.J.; Kuchroo, V.K.; Sharpe, A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med., 2009, 206(13), 3015-3029.
[http://dx.doi.org/10.1084/jem.20090847] [PMID: 20008522]
[47]
Xie, F.; Xu, M.; Lu, J.; Mao, L.; Wang, S. The role of exosomal PD-L1 in tumor progression and immunotherapy. Mol. Cancer, 2019, 18(1), 146.
[http://dx.doi.org/10.1186/s12943-019-1074-3] [PMID: 31647023]
[48]
Matsuzaki, J.; Gnjatic, S.; Mhawech-Fauceglia, P.; Beck, A.; Miller, A.; Tsuji, T.; Eppolito, C.; Qian, F.; Lele, S.; Shrikant, P.; Old, L.J.; Odunsi, K. Tumor-infiltrating NY-ESO-1–specific CD8 + T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl. Acad. Sci. USA, 2010, 107(17), 7875-7880.
[http://dx.doi.org/10.1073/pnas.1003345107] [PMID: 20385810]
[49]
Muenst, S.; Soysal, S.D.; Gao, F.; Obermann, E.C.; Oertli, D.; Gillanders, W.E. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res. Treat., 2013, 139(3), 667-676.
[http://dx.doi.org/10.1007/s10549-013-2581-3] [PMID: 23756627]
[50]
Sharma, P.; Allison, J.P. The future of immune checkpoint therapy. Science, 2015, 348(6230), 56-61.
[http://dx.doi.org/10.1126/science.aaa8172] [PMID: 25838373]
[51]
Boussiotis, V.A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med., 2016, 375(18), 1767-1778.
[http://dx.doi.org/10.1056/NEJMra1514296] [PMID: 27806234]
[52]
Tan, S.; Zhang, H.; Chai, Y.; Song, H.; Tong, Z.; Wang, Q.; Qi, J.; Wong, G.; Zhu, X.; Liu, W.J.; Gao, S.; Wang, Z.; Shi, Y.; Yang, F.; Gao, G.F.; Yan, J. An unexpected N-terminal loop in PD-1 dominates binding by nivolumab. Nat. Commun., 2017, 8(1), 14369.
[http://dx.doi.org/10.1038/ncomms14369] [PMID: 28165004]
[53]
Chen, L. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat. Rev. Immunol., 2004, 4(5), 336-347.
[http://dx.doi.org/10.1038/nri1349] [PMID: 15122199]
[54]
Intlekofer, A.M.; Thompson, C.B. At the Bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J. Leukoc. Biol., 2013, 94(1), 25-39.
[http://dx.doi.org/10.1189/jlb.1212621] [PMID: 23625198]
[55]
Lin, D.Y.; Tanaka, Y.; Iwasaki, M.; Gittis, A.G.; Su, H.P.; Mikami, B.; Okazaki, T.; Honjo, T.; Minato, N.; Garboczi, D.N. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc. Natl. Acad. Sci. USA, 2008, 105(8), 3011-3016.
[http://dx.doi.org/10.1073/pnas.0712278105] [PMID: 18287011]
[56]
Lázár-Molnár, E.; Yan, Q.; Cao, E.; Ramagopal, U.; Nathenson, S.G.; Almo, S.C. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc. Natl. Acad. Sci. USA, 2008, 105(30), 10483-10488.
[http://dx.doi.org/10.1073/pnas.0804453105] [PMID: 18641123]
[57]
Sharpe, A.H.; Pauken, K.E. The diverse functions of the PD1 inhibitory pathway. Nat. Rev. Immunol., 2018, 18(3), 153-167.
[http://dx.doi.org/10.1038/nri.2017.108] [PMID: 28990585]
[58]
Hui, E.; Cheung, J.; Zhu, J.; Su, X.; Taylor, M.J.; Wallweber, H.A.; Sasmal, D.K.; Huang, J.; Kim, J.M.; Mellman, I.; Vale, R.D. T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition. Science, 2017, 355(6332), 1428-1433.
[http://dx.doi.org/10.1126/science.aaf1292] [PMID: 28280247]
[59]
Patsoukis, N.; Brown, J.; Petkova, V.; Liu, F.; Li, L.; Boussiotis, V.A. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci. Signal., 2012, 5(230), ra46.
[http://dx.doi.org/10.1126/scisignal.2002796] [PMID: 22740686]
[60]
Inman, B.A.; Longo, T.A.; Ramalingam, S.; Harrison, M.R. Atezolizumab: A PD-L1–blocking antibody for bladder cancer. Clin. Cancer Res., 2017, 23(8), 1886-1890.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1417] [PMID: 27903674]
[61]
Sidaway, P. Skin cancer: Avelumab effective against Merkel-cell carcinoma. Nat. Rev. Clin. Oncol., 2016, 13(11), 652.
[PMID: 27670228]
[62]
Wilkinson, E. Nivolumab success in untreated metastatic melanoma. Lancet Oncol., 2015, 16(1), e9.
[http://dx.doi.org/10.1016/S1470-2045(14)71129-5] [PMID: 25638562]
[63]
Sun, C.; Mezzadra, R.; Schumacher, T.N. Regulation and function of the PD-L1 checkpoint. Immunity, 2018, 48(3), 434-452.
[http://dx.doi.org/10.1016/j.immuni.2018.03.014] [PMID: 29562194]
[64]
O’Sullivan Coyne, G.; Madan, R.A.; Gulley, J.L. Nivolumab: Promising survival signal coupled with limited toxicity raises expectations. J. Clin. Oncol., 2014, 32(10), 986-988.
[http://dx.doi.org/10.1200/JCO.2013.54.5996] [PMID: 24590655]
[65]
Shultz, D. Three Drugs Approved for Urothelial Carcinoma by FDA. Cancer Discov., 2017, 7(7), 659-660.
[http://dx.doi.org/10.1158/2159-8290.CD-NB2017-071] [PMID: 28546286]
[66]
Li, C.; Zhang, N.; Zhou, J.; Ding, C.; Jin, Y.; Cui, X.; Pu, K.; Zhu, Y. Peptide Blocking of PD-1/PD-L1 Interaction for Cancer Immunotherapy. Cancer Immunol. Res., 2018, 6(2), 178-188.
[http://dx.doi.org/10.1158/2326-6066.CIR-17-0035] [PMID: 29217732]
[67]
Sasikumar, P.; Ramachandra, M.; Vadlamani, S.; Shrimali, K.; Subbarao, K. Aurigene discovery technologies limited, assignee. Immunosuppression modulating compounds US Patent 8,907,053, December 9;2014
[68]
Chupak, L.S.; Zheng, X. Compounds useful as immunomodulators. Patent WO2018118848A1, 2018.
[69]
Gillman, K.W.; Goodrich, J.; Boy, K.M.; Zhang, Y.; Mapelli, C.; Poss, M.A.; Sun, L-Q.; Zhao, Q.; Mull, E.; Gillis, E.P. Macrocyclic peptides useful as immunomodulators. WO2016077518A1, 2016.
[70]
Sasikumar, P.; Ramachandra, M.; Naremaddepalli, S. VISTA signaling pathway inhibitory compounds useful as immunomodulators; Aurigene Discovery Technologies Limited, 2018.
[71]
Fang, W.; Zhang, J.; Hong, S.; Zhan, J.; Chen, N.; Qin, T.; Tang, Y.; Zhang, Y.; Kang, S.; Zhou, T.; Wu, X.; Liang, W.; Hu, Z.; Ma, Y.; Zhao, Y.; Tian, Y.; Yang, Y.; Xue, C.; Yan, Y.; Hou, X.; Huang, P.; Huang, Y.; Zhao, H.; Zhang, L. EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. Oncotarget, 2014, 5(23), 12189-12202.
[http://dx.doi.org/10.18632/oncotarget.2608] [PMID: 25361008]
[72]
Huang, M.Y.; Jiang, X.M.; Xu, Y.L.; Yuan, L.W.; Chen, Y.C.; Cui, G.; Huang, R.Y.; Liu, B.; Wang, Y.; Chen, X.; Lu, J.J. Platycodin D triggers the extracellular release of programed death Ligand-1 in lung cancer cells. Food Chem. Toxicol., 2019, 131, 110537.
[http://dx.doi.org/10.1016/j.fct.2019.05.045] [PMID: 31150782]
[73]
Azuma, K.; Ota, K.; Kawahara, A.; Hattori, S.; Iwama, E.; Harada, T.; Matsumoto, K.; Takayama, K.; Takamori, S.; Kage, M.; Hoshino, T.; Nakanishi, Y.; Okamoto, I. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann. Oncol., 2014, 25(10), 1935-1940.
[http://dx.doi.org/10.1093/annonc/mdu242] [PMID: 25009014]
[74]
Wang, C.W.; Klionsky, D.J. The molecular mechanism of autophagy. Mol. Med., 2003, 9(3-4), 65-76.
[http://dx.doi.org/10.1007/BF03402040] [PMID: 12865942]
[75]
Lim, S.O.; Li, C.W.; Xia, W.; Cha, J.H.; Chan, L.C.; Wu, Y.; Chang, S.S.; Lin, W.C.; Hsu, J.M.; Hsu, Y.H.; Kim, T.; Chang, W.C.; Hsu, J.L.; Yamaguchi, H.; Ding, Q.; Wang, Y.; Yang, Y.; Chen, C.H.; Sahin, A.A.; Yu, D.; Hortobagyi, G.N.; Hung, M.C. Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell, 2016, 30(6), 925-939.
[http://dx.doi.org/10.1016/j.ccell.2016.10.010] [PMID: 27866850]
[76]
Eikawa, S.; Nishida, M.; Mizukami, S.; Yamazaki, C.; Nakayama, E.; Udono, H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc. Natl. Acad. Sci. USA, 2015, 112(6), 1809-1814.
[http://dx.doi.org/10.1073/pnas.1417636112] [PMID: 25624476]
[77]
Cha, J.H.; Yang, W.H.; Xia, W.; Wei, Y.; Chan, L.C.; Lim, S.O.; Li, C.W.; Kim, T.; Chang, S.S.; Lee, H.H.; Hsu, J.L.; Wang, H.L.; Kuo, C.W.; Chang, W.C.; Hadad, S.; Purdie, C.A.; McCoy, A.M.; Cai, S.; Tu, Y.; Litton, J.K.; Mittendorf, E.A.; Moulder, S.L.; Symmans, W.F.; Thompson, A.M.; Piwnica-Worms, H.; Chen, C.H.; Khoo, K.H.; Hung, M.C. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol. Cell, 2018, 71(4), 606-620.e7.
[http://dx.doi.org/10.1016/j.molcel.2018.07.030] [PMID: 30118680]
[78]
Zanetti, G.; Pahuja, K.B.; Studer, S.; Shim, S.; Schekman, R. COPII and the regulation of protein sorting in mammals. Nat. Cell Biol., 2012, 14(1), 20-28.
[http://dx.doi.org/10.1038/ncb2390] [PMID: 22193160]
[79]
Viollet, B.; Guigas, B.; Garcia, N.S.; Leclerc, J.; Foretz, M.; Andreelli, F. Cellular and molecular mechanisms of metformin: An overview. Clin. Sci., 2012, 122(6), 253-270.
[http://dx.doi.org/10.1042/CS20110386] [PMID: 22117616]
[80]
A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma. Available From: https://ClinicalTrials.gov/show/NCT03006926
[81]
Live Biotherapeutic Product MRx0518 and Pembrolizumab Combination Study in Solid Tumors. Available From: https://ClinicalTrials.gov/show/NCT03637803
[82]
Evaluation of Safety and Activity of an Anti-PDL1 Antibody (DURVALUMAB) Combined With CSF-1R TKI (PEXIDARTINIB) in Patients With Metastatic/Advanced Pancreatic or Colorectal Cancers. Available From: https://ClinicalTrials.gov/show/NCT02777710
[83]
Sitravatinib (MGCD516) and Nivolumab in Oral Cavity Cancer Window Opportunity Study. Available From: https://ClinicalTrials.gov/show/NCT03575598
[84]
Basket combination study of inhibitors of DNA damage response, angiogenesis and programmed death ligand 1 in patients with advanced solid tumors. Available From: https://ClinicalTrials.gov/show/NCT03851614
[85]
Navtemadlin (KRT-232) with or without anti-PD-1/Anti-PD-L1 for the treatment of patients with merkel cell carcinoma. Available From: https://ClinicalTrials.gov/show/NCT03787602
[86]
Study of ipilimumab, nivolumab, and cabozantinib in patients with cutaneous melanoma. Available From: https://ClinicalTrials.gov/show/NCT05200143
[87]
Tomivosertib (eFT-508) in Combination With PD-1/PD-L1 Inhibitor Therapy. Available From: https://ClinicalTrials.gov/show/NCT03616834
[88]
THIO Sequenced With Cemiplimab in Advanced NSCLC. Available From: https://ClinicalTrials.gov/show/NCT05208944
[89]
Study with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive advanced/metastatic breast cancer. Available From: https://ClinicalTrials.gov/show/NCT04759248
[90]
A phase 1 study with ABBV-CLS-484 in subjects with locally advanced or metastatic tumors. Available From: https://ClinicalTrials.gov/show/NCT04777994
[91]
Effects of single agent niraparib and niraparib plus programmed cell death-1 (PD-1) inhibitors in non-small cell lung cancer participants. Available From: https://ClinicalTrials.gov/show/NCT03308942
[92]
Shaabani, S.; Gadina, L.; Surmiak, E.; Wang, Z.; Zhang, B.; Butera, R.; Zarganes-Tzitzikas, T.; Rodriguez, I.; Kocik-Krol, J.; Magiera-Mularz, K.; Skalniak, L.; Dömling, A.; Holak, T.A. Biphenyl ether analogs containing pomalidomide as small-molecule inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction. Molecules, 2022, 27(11), 3454.
[http://dx.doi.org/10.3390/molecules27113454] [PMID: 35684392]
[93]
Zhu, P.; Zhang, J.; Yang, Y.; Wang, L.; Zhou, J.; Zhang, H. Design, synthesis and biological evaluation of isoxazole-containing biphenyl derivatives as small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 immune checkpoint. Mol. Divers., 2022, 26(1), 245-264.
[http://dx.doi.org/10.1007/s11030-021-10208-4] [PMID: 33786726]
[94]
Song, Z.; Liu, B.; Peng, X.; Gu, W.; Sun, Y.; Xing, L.; Xu, Y.; Geng, M.; Ai, J.; Zhang, A. Design, synthesis, and pharmacological evaluation of Biaryl-Containing PD-1/PD-L1 interaction inhibitors bearing a unique difluoromethyleneoxy linkage. J. Med. Chem., 2021, 64(22), 16687-16702.
[http://dx.doi.org/10.1021/acs.jmedchem.1c01422] [PMID: 34761679]
[95]
Kim, E.H.; Kawamoto, M.; Dharmatti, R.; Kobatake, E.; Ito, Y.; Miyatake, H. Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 immune checkpoint interactions. Int. J. Mol. Sci., 2020, 21(10), 3639.
[http://dx.doi.org/10.3390/ijms21103639] [PMID: 32455628]
[96]
Zhang, H.; Xia, Y.; Yu, C.; Du, H.; Liu, J.; Li, H.; Huang, S.; Zhu, Q.; Xu, Y.; Zou, Y. Discovery of novel small-molecule inhibitors of PD-1/PD-L1 interaction via structural simplification strategy. Molecules, 2021, 26(11), 3347.
[http://dx.doi.org/10.3390/molecules26113347] [PMID: 34199417]
[97]
Cao, H.; Cheng, B.; Liu, T.; Chen, J. Synthesis and pharmacological evaluation of novel resorcinol biphenyl ether analogs as small molecule inhibitors of PD-1/PD-L1 with benign toxicity profiles for cancer treatment. Biochem. Pharmacol., 2021, 188, 114522.
[http://dx.doi.org/10.1016/j.bcp.2021.114522] [PMID: 33741334]
[98]
Wang, T.; Cai, S.; Wang, M.; Zhang, W.; Zhang, K.; Chen, D.; Li, Z.; Jiang, S. Novel biphenyl pyridines as potent small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 interaction. J. Med. Chem., 2021, 64(11), 7390-7403.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00010] [PMID: 34056906]
[99]
Sun, C.; Cheng, Y.; Liu, X.; Wang, G.; Min, W.; Wang, X.; Yuan, K.; Hou, Y.; Li, J.; Zhang, H.; Dong, H.; Wang, L.; Lou, C.; Sun, Y.; Yu, X.; Deng, H.; Xiao, Y.; Yang, P. Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents. Acta Pharm. Sin. B, 2022, 12(12), 4446-4457.
[http://dx.doi.org/10.1016/j.apsb.2022.04.007] [PMID: 36561991]
[100]
Wang, M.; Ma, X.; Zhou, K.; Mao, H.; Liu, J.; Xiong, X.; Zhao, X.; Narva, S.; Tanaka, Y.; Wu, Y.; Guo, C.; Sugiyama, H.; Zhang, W. Discovery of Pyrrole-imidazole Polyamides as PD-L1 expression inhibitors and their anticancer activity via immune and nonimmune pathways. J. Med. Chem., 2021, 64(9), 6021-6036.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00120] [PMID: 33949196]
[101]
Liu, A.; Dong, L.; Wei, X.L.; Yang, X.H.; Xiao, J.H.; Liu, Z.Q. Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor. Eur. J. Pharm. Sci., 2016, 88, 50-58.
[http://dx.doi.org/10.1016/j.ejps.2016.03.023] [PMID: 27063329]
[102]
Wang, F.; Ye, W.; Wang, S.; He, Y.; Zhong, H.; Wang, Y.; Zhu, Y.; Han, J.; Bing, Z.; Ji, S.; Liu, H.; Yao, X. Discovery of a new inhibitor targeting PD-L1 for cancer immunotherapy. Neoplasia, 2021, 23(3), 281-293.
[http://dx.doi.org/10.1016/j.neo.2021.01.001] [PMID: 33529880]
[103]
Chen, H.; Wang, K.; Yang, Y.; Huang, X.; Dai, X.; Feng, Z. Design, synthesis, and structure-activity relationship of programmed cell death-1/programmed cell death-ligand 1 interaction inhibitors bearing a benzo[d]isothiazole scaffold. Eur. J. Med. Chem., 2021, 217, 113377.
[http://dx.doi.org/10.1016/j.ejmech.2021.113377] [PMID: 33770574]
[104]
Wu, Y.; Zhang, Y.; Guo, Y.; Pan, Z.; Zhong, S.; Jin, X.; Zhuang, W.; Chen, S.; Gao, J.; Huang, W.; Dong, X.; Che, J. Discovery of phenyl-linked symmetric small molecules as inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction. Eur. J. Med. Chem., 2021, 223, 113637.
[http://dx.doi.org/10.1016/j.ejmech.2021.113637] [PMID: 34147746]
[105]
Yang, Y.; Wang, K.; Chen, H.; Feng, Z. Design, synthesis, evaluation, and SAR of 4-phenylindoline derivatives, a novel class of small-molecule inhibitors of the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. Eur. J. Med. Chem., 2021, 211, 113001.
[http://dx.doi.org/10.1016/j.ejmech.2020.113001] [PMID: 33272783]
[106]
Dai, X.; Wang, K.; Chen, H.; Huang, X.; Feng, Z. Design, synthesis, and biological evaluation of 1-methyl-1H-pyrazolo[4,3-b]pyridine derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction. Bioorg. Chem., 2021, 114, 105034.
[http://dx.doi.org/10.1016/j.bioorg.2021.105034] [PMID: 34116264]
[107]
Celano, M.; Schenone, S.; Cosco, D.; Navarra, M.; Puxeddu, E.; Racanicchi, L.; Brullo, C.; Varano, E.; Alcaro, S.; Ferretti, E.; Botta, G.; Filetti, S.; Fresta, M.; Botta, M.; Russo, D. Cytotoxic effects of a novel pyrazolopyrimidine derivative entrapped in liposomes in anaplastic thyroid cancer cells in vitro and in xenograft tumors in vivo. Endocr. Relat. Cancer, 2008, 15(2), 499-510.
[http://dx.doi.org/10.1677/ERC-07-0243] [PMID: 18509002]
[108]
Narva, S.; Xiong, X.; Ma, X.; Tanaka, Y.; Wu, Y.; Zhang, W. Synthesis and Evaluation of Biphenyl-1,2,3-Triazol-Benzonitrile Derivatives as PD-1/PD-L1 Inhibitors. ACS Omega, 2020, 5(33), 21181-21190.
[http://dx.doi.org/10.1021/acsomega.0c02916] [PMID: 32875254]
[109]
Kawashita, S.; Aoyagi, K.; Yamanaka, H.; Hantani, R.; Naruoka, S.; Tanimoto, A.; Hori, Y.; Toyonaga, Y.; Fukushima, K.; Miyazaki, S.; Hantani, Y. Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction. Bioorg. Med. Chem. Lett., 2019, 29(17), 2464-2467.
[http://dx.doi.org/10.1016/j.bmcl.2019.07.027] [PMID: 31351692]
[110]
Cheng, B.; Ren, Y.; Cao, H.; Chen, J. Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1. Eur. J. Med. Chem., 2020, 199, 112377.
[http://dx.doi.org/10.1016/j.ejmech.2020.112377] [PMID: 32388281]
[111]
Wang, Y.; Zhou, Y.; Cao, S.; Sun, Y.; Dong, Z.; Li, C.; Wang, H.; Yao, Y.; Yu, H.; Song, X.; Li, M.; Wang, J.; Wei, M.; Yang, G.; Yang, C. In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC). Bioorg. Chem., 2021, 111, 104833.
[http://dx.doi.org/10.1016/j.bioorg.2021.104833] [PMID: 33839580]
[112]
Liu, Y.; Zheng, M.; Ma, Z.; Zhou, Y.; Huo, J.; Zhang, W.; Liu, Y.; Guo, Y.; Zhou, X.; Li, H.; Chen, L. Design, synthesis, and evalua-tion of PD-L1 degraders to enhance T cell killing activity against melanoma. Chin. Chem. Lett., 2023, 34(5), 107762.
[http://dx.doi.org/10.1016/j.cclet.2022.107762]
[113]
Maruca, A.; Catalano, R.; Bagetta, D.; Mesiti, F.; Ambrosio, F.A.; Romeo, I.; Moraca, F.; Rocca, R.; Ortuso, F.; Artese, A.; Costa, G.; Alcaro, S.; Lupia, A. The Mediterranean Diet as source of bioactive compounds with multi-targeting anti-cancer profile. Eur. J. Med. Chem., 2019, 181, 111579.
[http://dx.doi.org/10.1016/j.ejmech.2019.111579] [PMID: 31398616]
[114]
Kim, J.H.; Kim, Y.S.; Choi, J.G.; Li, W.; Lee, E.J.; Park, J.W.; Song, J.; Chung, H.S. Kaempferol and Its Glycoside, Kaempferol 7-O-rhamnoside, Inhibit PD-1/PD-L1 interaction in vitro. Int. J. Mol. Sci., 2020, 21(9), 3239.
[http://dx.doi.org/10.3390/ijms21093239] [PMID: 32375257]
[115]
Choi, J.G.; Kim, Y.S.; Kim, J.H.; Kim, T.I.; Li, W.; Oh, T.W.; Jeon, C.H.; Kim, S.J.; Chung, H.S. Anticancer Effect of Salvia plebeia and Its Active Compound by Improving T-Cell Activity via Blockade of PD-1/PD-L1 interaction in humanized PD-1 mouse model. Front. Immunol., 2020, 11, 598556.
[http://dx.doi.org/10.3389/fimmu.2020.598556] [PMID: 33224152]
[116]
Li, W.; Kim, T.I.; Kim, J.H.; Chung, H.S. Immune Checkpoint PD-1/PD-L1 CTLA-4/CD80 are blocked by Rhus verniciflua stokes and its active compounds. Molecules, 2019, 24(22), 4062.
[http://dx.doi.org/10.3390/molecules24224062] [PMID: 31717574]
[117]
Bao, F.; Bai, H.Y.; Wu, Z.R.; Yang, Z.G. Phenolic compounds from cultivated Glycyrrhiza uralensis and their PD-1/PD-L1 inhibitory activities. Nat. Prod. Res., 2021, 35(4), 562-569.
[http://dx.doi.org/10.1080/14786419.2019.1586698] [PMID: 30908097]
[118]
Kim, J.H.; Kim, Y.S.; Kim, T.I.; Li, W.; Mun, J.G.; Jeon, H.D.; Kee, J.Y.; Choi, J.G.; Chung, H.S. Unripe black raspberry (Rubus coreanus Miquel) extract and its constitute, ellagic acid induces t cell activation and antitumor immunity by blocking PD-1/PD-L1 interaction. Foods, 2020, 9(11), 1590.
[http://dx.doi.org/10.3390/foods9111590] [PMID: 33147777]
[119]
Han, Y.; Gao, Y.; He, T.; Wang, D.; Guo, N.; Zhang, X.; Chen, S.; Wang, H. PD-1/PD-L1 inhibitor screening of caffeoylquinic acid compounds using surface plasmon resonance spectroscopy. Anal. Biochem., 2018, 547, 52-56.
[http://dx.doi.org/10.1016/j.ab.2018.02.003] [PMID: 29428377]
[120]
Sun, H.; Chen, D.; Zhan, S.; Wu, W.; Xu, H.; Luo, C.; Su, H.; Feng, Y.; Shao, W.; Wan, A.; Zhou, B.; Wan, G.; Bu, X. Design and discovery of natural cyclopeptide Skeleton based programmed death ligand 1 inhibitor as immune modulator for cancer therapy. J. Med. Chem., 2020, 63(19), 11286-11301.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01262] [PMID: 32844651]
[121]
Patil, S.P.; Yoon, S.C.; Aradhya, A.G.; Hofer, J.; Fink, M.A.; Enley, E.S.; Fisher, J.E.; Herb, M.C.; Klingos, A.; Proulx, J.T.; Fedorky, M.T. Macrocyclic compounds from ansamycin antibiotic class as inhibitors of PD1–PDL1 protein–protein interaction. Chem. Pharm. Bull., 2018, 66(8), 773-778.
[http://dx.doi.org/10.1248/cpb.c17-00800] [PMID: 30068796]
[122]
Abbas, A.; Lin, B.; Liu, C.; Morshed, A.; Hu, J.; Xu, H. Design and synthesis of A PD-1 binding peptide and evaluation of its anti-tumor activity. Int. J. Mol. Sci., 2019, 20(3), 572.
[http://dx.doi.org/10.3390/ijms20030572] [PMID: 30699956]
[123]
Miao, Q.; Zhang, W.; Zhang, K.; Li, H.; Zhu, J.; Jiang, S. Rational design of a potent macrocyclic peptide inhibitor targeting the PD-1/PD-L1 protein–protein interaction. RSC Advances, 2021, 11(38), 23270-23279.
[http://dx.doi.org/10.1039/D1RA03118J] [PMID: 35479790]
[124]
Li, Q.; Quan, L.; Lyu, J.; He, Z.; Wang, X.; Meng, J.; Zhao, Z.; Zhu, L.; Liu, X.; Li, H. Discovery of peptide inhibitors targeting human programmed death 1 (PD-1) receptor. Oncotarget, 2016, 7(40), 64967-64976.
[http://dx.doi.org/10.18632/oncotarget.11274] [PMID: 27533458]
[125]
Boohaker, R.J.; Sambandam, V.; Segura, I.; Miller, J.; Suto, M.; Xu, B. Rational design and development of a peptide inhibitor for the PD-1/PD-L1 interaction. Cancer Lett., 2018, 434, 11-21.
[http://dx.doi.org/10.1016/j.canlet.2018.04.031] [PMID: 29920293]