2. Academic Validation
  3. 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)

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

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.

Figures
Products