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)b enzamide (MGCD0103)

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 3; pp. 644 - 649
• Main Authors: Raeppel, Stephane, Zhou, Nancy, Gaudette, Frederic, Leit, Silvana, Paquin, Isabelle, Larouche, Guillaume, Moradei, Oscar, Frechette, Sylvie, Isakovic, Ljubomir, Delorme, Daniel, Fournel, Marielle, Kalita, Ann, Lu, Aihua, Trachy-Bourget, Marie-Claude, Yan, Pu Theresa, Liu, Jianhong, Rahil, Jubrail, Wang, James, Besterman, Jeffrey M, Murakami, Koji, Li, Zuomei, Vaisburg, Arkadii
• Format: Journal Article
• Language: English
• Published: 01.02.2009
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.048

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.