Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods

Pelz, Nicholas F.; Bian, Zhiguo; Zhao, Bin; Shaw, Subrata; Tarr, James C.; Belmar, Johannes; Gregg, Claire; Camper, DeMarco V.; Goodwin, Craig M.; Arnold, Allison L.; Sensintaffar, John L.; Friberg, Anders; Rossanese, Olivia W.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.5b01660

Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods

Journal Article · Wed Feb 24 00:00:00 EST 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.5b01660· OSTI ID:1247370

Pelz, Nicholas F. ^[1]; Bian, Zhiguo ^[1]; Zhao, Bin ^[1]; Shaw, Subrata ^[1]; Tarr, James C. ^[1]; Belmar, Johannes ^[1]; Gregg, Claire ^[1]; Camper, DeMarco V. ^[1]; Goodwin, Craig M. ^[1]; Arnold, Allison L. ^[1]; Sensintaffar, John L. ^[1]; Friberg, Anders ^[1]; Rossanese, Olivia W. ^[1]; Lee, Taekyu ^[1]; Olejniczak, Edward T. ^[1]; Fesik, Stephen W. ^[1]

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

Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. Additionally, X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Cancer Institute (NCI); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1247370

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 5 Vol. 59; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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