1402141-71-2Relevant academic research and scientific papers
A potent and highly efficacious Bcl-2/Bcl-xL inhibitor
Aguilar, Angelo,Zhou, Haibin,Chen, Jianfang,Liu, Liu,Bai, Longchuan,McEachern, Donna,Yang, Chao-Yie,Meagher, Jennifer,Stuckey, Jeanne,Wang, Shaomeng
, p. 3048 - 3067 (2013/05/22)
Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with Ki values of 50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression
Chen, Jianfang,Zhou, Haibin,Aguilar, Angelo,Liu, Liu,Bai, Longchuan,McEachern, Donna,Yang, Chao-Yie,Wang, Shaomeng,Meagher, Jennifer L.,Stuckey, Jeanne A.
, p. 8502 - 8514,13 (2020/09/15)
Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3- carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with Ki 50 values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.
