7YC9

Co-crystal structure of BTK kinase domain with inhibitor

Summary for 7YC9

• Entry DOI: 10.2210/pdb7yc9/pdb
• Descriptor: Tyrosine-protein kinase BTK, (7~{S})-2-(4-bromanyl-3,5-dimethoxy-phenyl)-7-(1-propanoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, complex, antitumor protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 31934.47

Authors

Zhou, X. (deposition date: 2022-07-01, release date: 2023-05-17, Last modification date: 2024-11-13)

Primary citation

Guo, Y.,Hu, N.,Liu, Y.,Zhang, W.,Yu, D.,Shi, G.,Zhang, B.,Yin, L.,Wei, M.,Yuan, X.,Luo, L.,Wang, F.,Song, X.,Xin, L.,Wei, Q.,Li, Y.,Guo, Y.,Chen, S.,Zhang, T.,Zhang, S.,Zhou, X.,Zhang, C.,Su, D.,Liu, J.,Cheng, Z.,Zhang, J.,Xing, H.,Sun, H.,Li, X.,Zhao, Y.,He, M.,Wu, Y.,Guo, Y.,Sun, X.,Tian, A.,Zhou, C.,Young, S.,Liu, X.,Wang, L.,Wang, Z.
Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases.
J.Med.Chem., 66:4025-4044, 2023

PubMed Abstract: Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (-) leads to a series of highly selective BTK inhibitors, in which - is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, - has been declared a preclinical candidate. However, - showed an inferior toxicity profile compared to that of -.

PubMed: 36912866
DOI: 10.1021/acs.jmedchem.2c01938

Experimental method

X-RAY DIFFRACTION (1.4 Å)