Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology

Bioorg Med Chem Lett. 2021 Jan 15:32:127717. doi: 10.1016/j.bmcl.2020.127717. Epub 2020 Nov 27.

Abstract

A hallmark of cancer is the evasion of apoptosis. Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulates the mitochondrial apoptosis pathway. Overexpression of MCL-1 contributes to oncogenesis and confers resistance to cancer treatments. Protein-protein interactions (PPI) are constitutive of the dynamic interplay between the pro- and anti-apoptotic proteins of the BCL-2 family, which is integral to controlling the apoptotic threshold of cells. Therapeutic intervention by small molecule BH3 mimetics to pharmacologically target the PPI and antagonize MCL-1 has made significant progress in recent years in oncology with multiple candidates entering clinical trials. This digest accounts the state-of-art MCL-1 inhibitors with emphasis on their discovery medicinal chemistry, highlighted in structure-based drug design (SBDD) and biological evaluations.

Keywords: Anti-survival/pro-apoptotic; Anticancer; BCL-2; MCL-1; MCL-1 inhibitor; Oncology; Pro-survival/anti-apoptotic; Protein-protein interactions; Structure-based drug design.

Publication types

  • Review

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / metabolism*
  • Drug Design
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Protein Interaction Maps / drug effects
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Apoptosis Regulatory Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Small Molecule Libraries