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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) |
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| Authors: | 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 Theresa Yan Jianhong Liu Jubrail Rahil James Wang Jeffrey M Besterman Koji Murakami Arkadii Vaisburg |
| Institution: | 1. MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1;2. MethylGene Inc., Department of Biology, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1;3. Taiho Pharmaceutical Co., Ltd, 1-27 Misugidai, Hanno-City, Saitama 357-8527, Japan |
| Abstract: | Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC50 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 p21WAF1/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. |
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