Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

Journal Article · Mon Dec 17 04:00:00 EST 2012 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm301448p· OSTI ID:1061312

Friberg, Anders ^[1]; Vigil, Dominico ^[1]; Zhao, Bin ^[1]; Daniels, R. Nathan ^[1]; Burke, Jason P. ^[1]; Garcia-Barrantes, Pedro M. ^[1]; Camper, DeMarco ^[1]; Chauder, Brian A. ^[1]; Lee, Taekyu ^[1]; Olejniczak, Edward T. ^[1]; Fesik, Stephen W. ^[1]

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1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)

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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• OSTI ID: 1061312
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: (1) ; 01, 2013 Vol. 56; ISSN 0022-2623
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: ENGLISH