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Title: 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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1061312
Resource Type:
Journal Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 56; Journal Issue: (1) ; 01, 2013; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Friberg, Anders, Vigil, Dominico, Zhao, Bin, Daniels, R. Nathan, Burke, Jason P., Garcia-Barrantes, Pedro M., Camper, DeMarco, Chauder, Brian A., Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design. United States: N. p., 2012. Web. doi:10.1021/jm301448p.
Friberg, Anders, Vigil, Dominico, Zhao, Bin, Daniels, R. Nathan, Burke, Jason P., Garcia-Barrantes, Pedro M., Camper, DeMarco, Chauder, Brian A., Lee, Taekyu, Olejniczak, Edward T., & Fesik, Stephen W. Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design. United States. https://doi.org/10.1021/jm301448p
Friberg, Anders, Vigil, Dominico, Zhao, Bin, Daniels, R. Nathan, Burke, Jason P., Garcia-Barrantes, Pedro M., Camper, DeMarco, Chauder, Brian A., Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. 2012. "Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design". United States. https://doi.org/10.1021/jm301448p.
@article{osti_1061312,
title = {Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design},
author = {Friberg, Anders and Vigil, Dominico and Zhao, Bin and Daniels, R. Nathan and Burke, Jason P. and Garcia-Barrantes, Pedro M. and Camper, DeMarco and Chauder, Brian A. and Lee, Taekyu and Olejniczak, Edward T. and Fesik, Stephen W.},
abstractNote = {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.},
doi = {10.1021/jm301448p},
url = {https://www.osti.gov/biblio/1061312}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = (1) ; 01, 2013,
volume = 56,
place = {United States},
year = {2012},
month = {12}
}