Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

  • Cell Death Dis. 2015 Jan 15;6(1):e1590. doi: 10.1038/cddis.2014.561.
J D Leverson  1 ,  H Zhang  1 ,  J Chen  1 ,  S K Tahir  1 ,  D C Phillips  1 ,  J Xue  1 ,  P Nimmer  1 ,  S Jin  1 ,  M Smith  1 ,  Y Xiao  1 ,  P Kovar  1 ,  A Tanaka  1 ,  M Bruncko  1 ,  G S Sheppard  1 ,  L Wang  1 ,  S Gierke  2 ,  L Kategaya  2 ,  D J Anderson  2 ,  C Wong  2 ,  J Eastham-Anderson  2 ,  M J C Ludlam  2 ,  D Sampath  2 ,  W J Fairbrother  2 ,  I Wertz  2 ,  S H Rosenberg  1 ,  C Tse  1 ,  S W Elmore  1 ,  A J Souers  1
Affiliations
  • 1. Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
  • 2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
PMID: 25590800 DOI: 10.1038/cddis.2014.561
Abstract

The anti-apoptotic protein Mcl-1 is a key regulator of Cancer cell survival and a known resistance factor for small-molecule Bcl-2 Family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit Mcl-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to Mcl-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic Apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung Cancer cell lines demonstrated to be Mcl-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the Bcl-2/Bcl-xL Inhibitor navitoclax to kill a variety of Cancer cell lines. This work represents the first description of small-molecule Mcl-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of Mcl-1 and the promise of small-molecule Mcl-1 inhibitors as potential therapeutics for the treatment of Cancer.

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