SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103)

  • Bioorg Med Chem Lett. 2009 Feb 1;19(3):644-9. doi: 10.1016/j.bmcl.2008.12.048.
Stéphane Raeppel  1 ,  Nancy Zhou ,  Frédéric Gaudette ,  Silvana Leit ,  Isabelle Paquin ,  Guillaume Larouche ,  Oscar Moradei ,  Sylvie Fréchette ,  Ljubomir Isakovic ,  Daniel Delorme ,  Marielle Fournel ,  Ann Kalita ,  Aihua Lu ,  Marie-Claude Trachy-Bourget ,  Pu Theresa Yan ,  Jianhong Liu ,  Jubrail Rahil ,  James Wang ,  Jeffrey M Besterman ,  Koji Murakami ,  Zuomei Li ,  Arkadii Vaisburg
Affiliations
  • 1. MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1. [email protected]
PMID: 19114304 DOI: 10.1016/j.bmcl.2008.12.048
Abstract

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit Recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human Cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.