Faculty Opinions recommendation of Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.

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. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of < 100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers. PMID: 23244564 Funding information This work was supported by: NCI NIH HHS, United States Grant ID: DP1CA174419 NIH HHS, United States Grant ID: DP1OD006933 NCI NIH HHS, United States Grant ID: P50 CA098131 NCRR NIH HHS, United States Grant ID: 1S10RR025677-01 NIH HHS, United States Grant ID: DP1 OD006933 NCI NIH HHS, United States Grant ID: P50CA098131 NCI NIH HHS, United States Grant ID: RC2 CA148375 CCR NIH HHS, United States Grant ID: RC2A148375 NCRR NIH HHS, United States Grant ID: S10 RR025677 NCI NIH HHS, United States Grant ID: DP1 CA174419 More Less keyboard_arrow_down