Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains

Bioorg Med Chem. 2017 Jan 1;25(1):138-152. doi: 10.1016/j.bmc.2016.10.020. Epub 2016 Oct 18.

Abstract

As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki=0.077μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki=0.18μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki=8.45μM), which was the same as positive control Gossypol (Ki=7.54μM).

Keywords: Bcl-2; Cancer; Mcl-1; Pyrrolidine; Target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gossypol / pharmacology
  • Humans
  • Molecular Docking Simulation
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neoplasms / drug therapy
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*

Substances

  • Antineoplastic Agents
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrrolidines
  • Gossypol