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

Abstract

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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
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  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Cancer Institute (NCI)
OSTI Identifier:
1247370
Grant/Contract Number:  
DP1OD006933/DP1CA174419; HHSN261200800001E; P50CA098131; 1S-10RR025677-01; AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 5; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Chemical structure; Inhibitors; Screening assays; Probes; Group 13 compounds

Citation Formats

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., and Fesik, Stephen W. Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.5b01660.
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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. Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods. United States. https://doi.org/10.1021/acs.jmedchem.5b01660
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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., and Fesik, Stephen W. Wed . "Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods". United States. https://doi.org/10.1021/acs.jmedchem.5b01660. https://www.osti.gov/servlets/purl/1247370.
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@article{osti_1247370,
title = {Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods},
author = {Pelz, Nicholas F. and Bian, Zhiguo and Zhao, Bin and Shaw, Subrata and Tarr, James C. and Belmar, Johannes and Gregg, Claire and Camper, DeMarco V. and Goodwin, Craig M. and Arnold, Allison L. and Sensintaffar, John L. and Friberg, Anders and Rossanese, Olivia W. and Lee, Taekyu and Olejniczak, Edward T. and Fesik, Stephen W.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.5b01660},
journal = {Journal of Medicinal Chemistry},
number = 5,
volume = 59,
place = {United States},
year = {Wed Feb 24 00:00:00 EST 2016},
month = {Wed Feb 24 00:00:00 EST 2016}
}
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Publisher's Version of Record
https://doi.org/10.1021/acs.jmedchem.5b01660
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