Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

Cell Death Dis. 2015 Jan 15;6(1):e1590. doi: 10.1038/cddis.2014.561.

Abstract

The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Synergism
  • Humans
  • Indoles / pharmacology
  • Membrane Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neoplasms / pathology*
  • Proto-Oncogene Proteins / metabolism
  • Small Molecule Libraries / pharmacology*
  • Sulfonamides / pharmacology*

Substances

  • Aniline Compounds
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Indoles
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins
  • Small Molecule Libraries
  • Sulfonamides
  • indole-2-carboxylic acid
  • navitoclax