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Discovery of N -(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an Orally Active Histone Deacetylase Inhibitor

2008; American Chemical Society; Volume: 51; Issue: 14 Linguagem: Inglês

10.1021/jm800251w

1520-4804

Nancy Zhou, Oscar Moradei, Stéphane Raeppel, Silvana Leit, Sylvie Fréchette, Frédéric Gaudette, Isabelle Paquin, Naomy Bernstein, Giliane Bouchain, Arkadii Vaisburg, Zhiyun Jin, J. H. Gillespie, Jinru Wang, Marielle Fournel, Pu Yan, Marie-Claude Trachy-Bourget, Ann Kalita, Aihua Lu, Jubrail Rahil, A. Robert MacLeod, Zuomei Li, Jeffrey M. Besterman, Daniel Delorme,

Protein Degradation and Inhibitors

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.