1. Abstract 2350: Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design
- Author
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R. Nathan Daniels, Brian A. Chauder, Pedro M. Garcia-Barrantes, Jason P. Burke, Anders Friberg, Lee Taekyu, Dominico Vigil, Edward T. Olejniczak, Fesik Stephen W, DeMarco Camper, and Bin Zhao
- Subjects
Cancer Research ,Myeloid ,Chemistry ,Cell ,Cancer ,medicine.disease ,Small molecule ,Dissociation constant ,Leukemia ,medicine.anatomical_structure ,Molecular recognition ,Oncology ,Apoptosis ,hemic and lymphatic diseases ,medicine ,Cancer research - Abstract
Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Overexpression of Mcl-1 is also a resistance mechanism that prevents tumor cells from being effectively treated by existing chemotherapies. Thus, inhibition of Mcl-1 is a promising therapeutic strategy for the treatment of cancer. However, Mcl-1 exerts its effects through protein-protein interactions and is thought to be very challenging to target with small molecules. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. From an NMR-based screen of a large fragment library, over 130 hits were identified. Two distinct chemical hit series were found that bind to two different sites on Mcl-1 as revealed by NMR-derived model structures. Members of the two fragment classes were merged together to produce compounds that bind to Mcl-1 with greater than two orders of magnitude improved binding affinity. Structures of these compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition involved in small-molecule binding to Mcl-1. Lead compounds exhibited a dissociation constant of Citation Format: Taekyu Lee, Anders Friberg, Dominico Vigil, Bin Zhao, R. Nathan Daniels, Jason P. Burke, Pedro M. Garcia-Barrantes, DeMarco Camper, Brian A. Chauder, Edward T. Olejniczak, Stephen W. Fesik. Discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2350. doi:10.1158/1538-7445.AM2013-2350
- Published
- 2013