Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.

Burke JP, Bian Z, Shaw S, Zhao B, Goodwin CM, Belmar J, Browning CF, Vigil D, Friberg A, Camper DV, Rossanese OW, Lee T, Olejniczak ET, Fesik SW
J Med Chem. 2015 58 (9): 3794-805

PMID: 25844895 · PMCID: PMC5565203 · DOI:10.1021/jm501984f

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.

MeSH Terms (11)

bcl-X Protein Crystallography, X-Ray Heterocyclic Compounds, 3-Ring Humans Indoles K562 Cells Models, Molecular Molecular Conformation Myeloid Cell Leukemia Sequence 1 Protein Protein Binding Structure-Activity Relationship

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