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Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

ABSTRACT: Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. PDB ID CODES:Comp. 2: 5IEZ; Comp. 5: 5IF4.

SUBMITTER: Lee T

PROVIDER: S-EPMC5381274 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Lee Taekyu T Bian Zhiguo Z Zhao Bin B Hogdal Leah J LJ Sensintaffar John L JL Goodwin Craig M CM Belmar Johannes J Shaw Subrata S Tarr James C JC Veerasamy Nagarathanam N Matulis Shannon M SM Koss Brian B Fischer Melissa A MA Arnold Allison L AL Camper DeMarco V DV Browning Carrie F CF Rossanese Olivia W OW Budhraja Amit A Opferman Joseph J Boise Lawrence H LH Savona Michael R MR Letai Anthony A Olejniczak Edward T ET Fesik Stephen W SW

FEBS letters 20161219 1

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. Thes ...[more]

PMID: 27878989

Dataset Information

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Publications

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

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