2. Academic Validation
  3. 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)

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

Affiliation

  • 1 MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1. raeppels@methylgene.com
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.

Figures