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)

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.

Graphical abstractAnalogues of the clinical compound MGCD0103 (A) were designed, synthesized, and evaluated in multiple in vitro assays. Lead molecule of the series, compound 25 showed significant anti-tumor activity in vivo in different mouse tumor xenograft models upon oral dosing.Figure optionsDownload full-size imageDownload as PowerPoint slide