Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein

Bioorg Med Chem Lett. 2014 Mar 15;24(6):1484-8. doi: 10.1016/j.bmcl.2014.02.010. Epub 2014 Feb 14.


Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts.

Keywords: Apoptosis; BCL; FBDD; FBLD; Fragment-based; MCL-1; NMR.

MeSH terms

  • Binding Sites
  • Biphenyl Compounds / chemistry
  • Crystallography, X-Ray
  • Drug Design*
  • Magnetic Resonance Spectroscopy
  • Molecular Dynamics Simulation
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Salicylic Acid / chemistry
  • Salicylic Acid / metabolism
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism


  • Biphenyl Compounds
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Sulfonamides
  • diphenyl
  • Salicylic Acid