6J6M

Co-crystal structure of BTK kinase domain with Zanubrutinib

Summary for 6J6M

• Entry DOI: 10.2210/pdb6j6m/pdb
• Descriptor: Tyrosine-protein kinase BTK, (7S)-2-(4-phenoxyphenyl)-7-(1-propanoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, IMIDAZOLE, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31894.64

Authors

Zhou, X.,Hong, Y. (deposition date: 2019-01-15, release date: 2019-10-23, Last modification date: 2024-10-23)

Primary citation

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., 62:7923-7940, 2019

PubMed Abstract: Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound (, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.

PubMed: 31381333
DOI: 10.1021/acs.jmedchem.9b00687

Experimental method

X-RAY DIFFRACTION (1.25 Å)