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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)

2008; Elsevier BV; Volume: 19; Issue: 3 Linguagem: Inglês

10.1016/j.bmcl.2008.12.048

1464-3405

Stéphane Raeppel, 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 Yan, Jianhong Liu, Jubrail Rahil, Jinru Wang, Jeffrey M. Besterman, Koji Murakami, Zuomei Li, Arkadii Vaisburg,

Peptidase Inhibition and Analysis

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.