Discovery and development of substituted tyrosine derivatives as Bcl-2/Mcl-1 inhibitors

Bioorg Med Chem. 2018 Sep 15;26(17):4907-4915. doi: 10.1016/j.bmc.2018.08.030. Epub 2018 Aug 24.

Abstract

Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound 1 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a Ki value of 5.2 µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-XL protein. Promisingly, compound 6i inhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with a Ki value of 450 and 190 nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.

Keywords: Anti-tumor; Apoptosis; Bcl-2; Mcl-1; Tyrosine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon-13 Magnetic Resonance Spectroscopy
  • Cell Proliferation / drug effects
  • Drug Discovery*
  • Humans
  • Jurkat Cells
  • Mass Spectrometry
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proton Magnetic Resonance Spectroscopy
  • Tyrosine / chemistry*
  • Tyrosine / metabolism
  • Tyrosine / pharmacology*

Substances

  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Tyrosine