Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477

Cell Death & Disease
David J MallickAlan Eastman

Abstract

Targeting anti-apoptotic BCL2 family proteins has become an attractive therapeutic strategy for many cancers, and the BCL2-selective inhibitor ABT-199 (venetoclax) has obtained clinical success. However, MCL1 can promote drug resistance and overall cancer cell survival. Thus, there is a critical need to develop an effective drug that antagonizes MCL1. However, most putative MCL1 inhibitors have been misclassified as they fail to directly inhibit MCL1 in cells, but rather induce the pro-apoptotic protein NOXA. We have investigated three putative MCL1 inhibitors: MIM1, UMI-77, and A-1210477. All three compounds were developed in cell-free assays and then found to be cytotoxic, and hence assumed to directly target MCL1 in cells. Here, we investigated whether these compounds directly inhibit MCL1 or inhibit MCL1 indirectly through the induction of NOXA. Both MIM1- and UMI-77-induced NOXA through the unfolded protein response pathway, and sensitized leukemia cells to ABT-199; this cytotoxicity was dependent on NOXA suggesting that these compounds do not directly target MCL1. A-1210477 was the only compound that did not induce NOXA, but it still sensitized cells to ABT-199. A-1210477 induced accumulation of MCL1 protein consistent wi...Continue Reading

References

Jan 23, 1999·Cell Death and Differentiation·B SingleP Nicotera
Nov 7, 2001·The Journal of Experimental Medicine·G Q WangH Rabinowich
Mar 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Peter E CzabotarPeter M Colman
Dec 18, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kenji OkumuraFrank A Sinicrope
Jan 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Qiuyan WangYihong Ye
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Dec 17, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Keryn M LucasJohn D Allen
Jul 9, 2013·Cell Death and Differentiation·S VaradarajanG M Cohen
Sep 11, 2013·Molecular Cancer Therapeutics·Fardokht AbulwerdiZaneta Nikolovska-Coleska
May 9, 2014·The Journal of Biological Chemistry·Xiaming PangXu Luo
Nov 16, 2014·Apoptosis : an International Journal on Programmed Cell Death·Marc Kvansakul, Mark G Hinds
Jun 5, 2016·Drugs·Emma D Deeks
Aug 19, 2016·Molecular Cancer Therapeutics·Ryan S Soderquist, Alan Eastman
Oct 28, 2016·Nature·András KotschyOlivier Geneste
Dec 3, 2016·PloS One·Hilmar QuentmeierRose-Marie Amini
Apr 12, 2017·Seminars in Cell & Developmental Biology·Richard W Birkinshaw, Peter E Czabotar
Jul 30, 2017·The FEBS Journal·Aida Peña-Blanco, Ana J García-Sáez

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Citations

Oct 22, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Ying ShenYaru Sun
Jun 4, 2020·International Journal of Molecular Sciences·Liang-Jun WangLong-Sen Chang
Jul 25, 2019·Cell Death and Differentiation·Mariana Villalobos-OrtizAnthony Letai
Feb 13, 2021·Biomolecules·Kelly FéralChristian Touriol
Feb 19, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Sarah Kehr, Meike Vogler
Aug 6, 2021·Frontiers in Pharmacology·Omar Al-OdatManoj Pandey
Sep 14, 2021·Biochemical Society Transactions·Erinna F Lee, W Douglas Fairlie

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Datasets Mentioned

BETA
ABT-199

Methods Mentioned

BETA
protein assay
electrophoresis
PCR
transfection
flow cytometry

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