Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor

  • J Med Chem. 2008 Jul 24;51(14):4072-5. doi: 10.1021/jm800251w.
Nancy Zhou  1 ,  Oscar Moradei ,  Stephane Raeppel ,  Silvana Leit ,  Sylvie Frechette ,  Frederic Gaudette ,  Isabelle Paquin ,  Naomy Bernstein ,  Giliane Bouchain ,  Arkadii Vaisburg ,  Zhiyun Jin ,  Jeff Gillespie ,  James Wang ,  Marielle Fournel ,  Pu T Yan ,  Marie-Claude Trachy-Bourget ,  Ann Kalita ,  Aihua Lu ,  Jubrail Rahil ,  A Robert MacLeod ,  Zuomei Li ,  Jeffrey M Besterman ,  Daniel Delorme
Affiliations
  • 1. MethylGene Inc., 7220 Frederick-Banting, Montréal, Québec H4S 2A1, Canada.
PMID: 18570366 DOI: 10.1021/jm800251w
Abstract

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks Cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and Apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an Anticancer drug.