Title : Structure-Based Design of Highly Potent and Efficacious Bcl-2 and Bcl-xL Inhibitors as New Anticancer Agents

Speaker: Haibin Zhou, Research Investigator, Internal of Medicine and Comprehensive Cancer Center, University of Michigan.

Host: Prof. Mingyao Liu

When: 2013-01-09 14:00

Where: Conference Room 534, School of Life Sciences

Abstract：

Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. A 1.4 ? resolution crystal structure of a lead compound, BM-702, complexed with Bcl-xL has provided a basis for our further optimization. Our efforts accumulated into the design of compound BM-1197, which binds to Bcl-2 and Bcl-xL with IC50 < 5 nM and has low nanomolar IC50 values in cell growth inhibition in cancer cell lines. Significantly, BM-1197 achieves rapid, complete, and durable tumor regression in the H146 and H1963 small-cell lung cancer xenograft model at a well-tolerated dose schedule. An analogue of BM-1197 has been selected for IND-enabling studies.