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

ABSTRACT: 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.

SUBMITTER: Burke JP 

PROVIDER: S-EPMC5565203 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Burke Jason P JP   Bian Zhiguo Z   Shaw Subrata S   Zhao Bin B   Goodwin Craig M CM   Belmar Johannes J   Browning Carrie F CF   Vigil Dominico D   Friberg Anders A   Camper DeMarco V DV   Rossanese Olivia W OW   Lee Taekyu T   Olejniczak Edward T ET   Fesik Stephen W SW  

Journal of medicinal chemistry 20150417 9

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 c  ...[more]

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