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Author Notes:

Corresponding Author: Stephen.Fesik@Vanderbilt.Edu

The authors thank co-workers at the High-Throughput Screening Core facility of Vanderbilt University, TN, for compound management and Nicolas Pelz for useful discussions.

The authors declare no competing financial interest.

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Research Funding:

This research was supported by the U.S. National Institutes of Health, NIH Director’s Pioneer Award DP1OD006933/DP1CA174419 to S.W.F., The NCI Experimental Therapeutics (NExT) Program BOA29XS129TO22 under the Leidos Biomed Prime Contract No. HHSN261200800001E, and a career development award to S.W.F. from a NCI SPORE grant in breast cancer (Grant P50CA098131) to C. L. Arteaga.

The Biomolecular NMR Facility at Vanderbilt University is supported in part by a NIH SIG Grant 1S-10RR025677-01 and Vanderbilt University matching funds.

Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Biophysics
  • Cell Biology
  • apoptosis
  • cancer
  • drug discovery
  • myeloid cell leukemia 1
  • structure-based drug design
  • FRAGMENT-BASED METHODS
  • STRUCTURE-BASED DESIGN
  • MCL-1 INHIBITORS
  • CANCER-THERAPY
  • STRUCTURAL-ANALYSIS
  • TARGETING MCL-1
  • HIGH-AFFINITY
  • BCL-2
  • PROTEIN
  • SPECIFICITY

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

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Journal Title:

FEBS Letters

Volume:

Volume 591, Number 1

Publisher:

, Pages 240-251

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 Federation of European Biochemical Societies

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