Abstract
Bruton’s tyrosine kinase (BTK) plays a vital role in B-cell antigen receptor (BCR) signalling
transduction pathway. Controlling BCR signalling by BTK inhibitors is a promising therapeutic
approach for the treatment of inflammatory and autoimmune diseases. Since the approval of
ibrutinib for the treatment of different haematological cancers in 2013, great efforts have been made
to explore new BTK inhibitors. Despite the remarkable potency and efficacy of first and second
generation irreversible BTK inhibitors against various lymphomas and leukaemia, there are also
some clinical limitations, such as off-target toxicity and primary/acquired drug resistance. Acquired
drug resistance due to the C481S mutation in BTK is the major challenging problem of irreversible
inhibitors. After, the BTK C481S mutation, the irreversible covalent inhibitors cannot form covalent
bond with BTK and drop activities. Hence, there is an urgent need to develop novel BTK inhibitors
to overcome the mutation problem. In recent years, a few reversible BTK inhibitors have been developed
and are under clinical evaluation stages. In addition, a few reversible BTK-PROTACs have
been explored and under developments. A number of reversible non-covalent BTK inhibitors, including
MK1026/ ARQ531, LOXO305, fenebrutinib are at different stages of clinical trials for autoimmune
diseases. In this review, we summarized the discovery and development of nextgeneration
BTK inhibitors, especially targeting BTK C481S mutation and their applications for the
treatment of lymphomas and autoimmune diseases.
Keywords:
Bruton’s tyrosine kinase, BCR signalling, Irreversible inhibitor, Reversible inhibitor, PROTAC, Xenografts, Anticancer.
Graphical Abstract
[44]
Guo, Y.; Liu, Y.; Hu, N.; Yu, D.; Zhou, C.; Shi, G.; Zhang, B.; Wei, M.; Liu, J.; Luo, L.; Tang, Z.; Song, H.; Guo, Y.; Liu, X.; Su, D.; Zhang, S.; Song, X.; Zhou, X.; Hong, Y.; Chen, S.; Cheng, Z.; Young, S.; Wei, Q.; Wang, H.; Wang, Q.; Lv, L.; Wang, F.; Xu, H.; Sun, H.; Xing, H.; Li, N.; Zhang, W.; Wang, Z.; Liu, G.; Sun, Z.; Zhou, D.; Li, W.; Liu, L.; Wang, L.; Wang, Z. Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of bruton’s tyrosine kinase.
J. Med. Chem., 2019,
62(17), 7923-7940.
[
http://dx.doi.org/10.1021/acs.jmedchem.9b00687] [PMID:
31381333]
[53]
Watterson, S.H.; Liu, Q.; Beaudoin Bertrand, M.; Batt, D.G.; Li, L.; Pattoli, M.A.; Skala, S.; Cheng, L.; Obermeier, M.T.; Moore, R.; Yang, Z.; Vickery, R.; Elzinga, P.A.; Discenza, L.; D’Arienzo, C.; Gillooly, K.M.; Taylor, T.L.; Pulicicchio, C.; Zhang, Y.; Heimrich, E.; McIntyre, K.W.; Ruan, Q.; Westhouse, R.A.; Catlett, I.M.; Zheng, N.; Chaudhry, C.; Dai, J.; Galella, M.A.; Tebben, A.J.; Pokross, M.; Li, J.; Zhao, R.; Smith, D.; Rampulla, R.; Allentoff, A.; Wallace, M.A.; Mathur, A.; Salter-Cid, L.; Macor, J.E.; Carter, P.H.; Fura, A.; Burke, J.R.; Tino, J.A. Discovery of Branebrutinib (BMS-986195): A strategy for identifying a highly potent and selective covalent inhibitor providing rapid in vivo inactivation of Bruton’s Tyrosine Kinase (BTK).
J. Med. Chem., 2019,
62(7), 3228-3250.
[
http://dx.doi.org/10.1021/acs.jmedchem.9b00167] [PMID:
30893553]
[65]
Fabian, C.A.; Reiff, S.D.; Guinn, D.; Neuman, L.; Fox, J.A.; Wilson, W.; Byrd, J.C.; Woyach, J.A.; Johnson, A.J. SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits c481s mutated bruton tyrosine kinase. Proc. Exper. Mol. Ther., 2017, 1207, 1207.
[69]
Eathiraj, S.; Yu, Y.; Savage, R.; Woyach, J.A.; Reiff, S.D.; Johnson, A.J.; Schwartz, B. ARQ 531, a potent reversible BTK inhibitor, exhibits potent antitumor activity in Ibrutinib-resistant diffuse large B-Cell lymphoma.Proc. Exper. Mol. Therapeut; , 2018, 1963, pp. 1963-1963.
[74]
Jebaraj, B.M.C.; Müller, A.; Dheenadayalan, R.P.; Endres, S.; Roessner, P.M.; Seyfried, F.; Walliser, C.; Wist, M.; Qi, J.; Tausch, E.; Mertens, D.; Fox, J.A.; Debatin, K-M.; Meyer, L.H.; Taverna, P.; Seiffert, M.; Gierschik, P.; Stilgenbauer, S. Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia. Blood, 2002, 139(6), 859-875.
[82]
Hong, J.; Xu, X.; Le, X. Pyrazolopyrimidine derivative, manufacturing method, pharmaceutical composition and use thereof., Patent WO 2016 154998, 2016.
[84]
Xie, L.; Qiao, D.; Das, D. Small molecule inhibitors of BTK and/or mutant C481S of BTK. CN112574200A, 2021.
[102]
Troup, R.I.; Fallan, C.; Baud, M.G.J. Current strategies for the design of PROTAC linkers: A critical review. Explor. Target. Anti-tumor Ther., 2020, 1, 273-312.
[117]
Qian, M.; Ye, F.; Zhang, C.; Wang, J.; Zhang, Y.; Cui, Y.; Li, L.; Gou, X.; Ni, J. Abstract 3761: HSK26784: An oral PROTACBTK degrader for multiple B Lymphocyte derived malignancies.Proc. Immunol; , 2020, pp. 3761-3761.
,
Jingbing Wang and
Jian Hong
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