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

FEBS Lett. 2017 Jan;591(1):240-251. doi: 10.1002/1873-3468.12497. Epub 2016 Dec 19.


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.

Keywords: apoptosis; cancer; drug discovery; myeloid cell leukemia 1; structure-based drug design.

Publication types

  • Letter

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Bcl-2-Like Protein 11 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Design
  • Drug Discovery
  • Humans
  • Immunoprecipitation
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • bcl-X Protein / metabolism


  • Antineoplastic Agents
  • Bcl-2-Like Protein 11
  • Myeloid Cell Leukemia Sequence 1 Protein
  • bcl-X Protein