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

Bioorganic & Medicinal Chemistry
Renshuai LiuHao Fang

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.

References

Aug 25, 2004·Analytical Biochemistry·Zaneta Nikolovska-ColeskaShaomeng Wang
Mar 27, 2007·Cell·Kylie D MasonBenjamin T Kile
Nov 16, 2014·Apoptosis : an International Journal on Programmed Cell Death·Marc Kvansakul, Mark G Hinds
Mar 6, 2015·British Journal of Cancer·J Lopez, S W G Tait
May 9, 2015·Cell Death and Differentiation·A R D Delbridge, A Strasser
Aug 19, 2016·Molecular Cancer Therapeutics·Ryan S Soderquist, Alan Eastman
Apr 12, 2017·Seminars in Cell & Developmental Biology·Richard W Birkinshaw, Peter E Czabotar
Jul 6, 2017·Biochemical and Biophysical Research Communications·Frank Edlich

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