8HTR

Crystal structure of Bcl2 in complex with S-9c

Summary for 8HTR

• Entry DOI: 10.2210/pdb8htr/pdb
• Descriptor: Apoptosis regulator Bcl-2, 4-[4-[(2~{S})-2-(2-chlorophenyl)pyrrolidin-1-yl]phenyl]-~{N}-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1~{H}-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (3 entities in total)
• Functional Keywords: inhibitor, apoptosis
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 20576.32

Authors

Liu, J.,Xu, M.,Feng, Y.,Liu, Y. (deposition date: 2022-12-21, release date: 2024-05-15, Last modification date: 2024-06-05)

Primary citation

Guo, Y.,Xue, H.,Hu, N.,Liu, Y.,Sun, H.,Yu, D.,Qin, L.,Shi, G.,Wang, F.,Xin, L.,Sun, W.,Zhang, F.,Song, X.,Li, S.,Wei, Q.,Guo, Y.,Li, Y.,Liu, X.,Chen, S.,Zhang, T.,Wu, Y.,Su, D.,Zhu, Y.,Xu, A.,Xu, H.,Yang, S.,Zheng, Z.,Liu, J.,Yang, X.,Yuan, X.,Hong, Y.,Sun, X.,Guo, Y.,Zhou, C.,Liu, X.,Wang, L.,Wang, Z.
Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.
J.Med.Chem., 67:7836-7858, 2024

PubMed Abstract: The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound , sonrotoclax), which exhibits strong and inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-x without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

PubMed: 38695063
DOI: 10.1021/acs.jmedchem.4c00027

Experimental method

X-RAY DIFFRACTION (1.6 Å)