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

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 m...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-03, Vol.59 (5), p.2054-2066
Main Authors: 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
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Chemical structure
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery
Group 13 compounds
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Inhibitors
Models, Molecular
Molecular Structure
Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
Probes
Screening assays
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary: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. 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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.5b01660