Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.

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.

[1]  S. Horinouchi,et al.  Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase , 1999, Oncogene.

[2]  A. Kalita,et al.  (2-Amino-phenyl)-amides of ω-substituted alkanoic acids as new histone deacetylase inhibitors , 2004 .

[3]  A. Kalita,et al.  Substituted N-(2-aminophenyl)-benzamides, (E)-N-(2-aminophenyl)-acrylamides and their analogues: novel classes of histone deacetylase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[4]  R. Sullivan,et al.  Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[6]  P. Liberator,et al.  Histone deacetylase: a target for antiproliferative and antiprotozoal agents. , 2001, Current medicinal chemistry.

[7]  A. Kalita,et al.  Design and synthesis of 4-[(s-triazin-2-ylamino)methyl]-N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[8]  Daniel Delorme,et al.  Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. , 2003, Journal of medicinal chemistry.

[9]  T. Suzuki,et al.  Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. , 1999, Journal of medicinal chemistry.

[10]  T. Tsuruo,et al.  A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Minden,et al.  Clinical activity and safety of the histone deacetylase inhibitor MGCD0103: Results of a phase I study in patients with leukemia or myelodysplastic syndromes (MDS). , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  T. Kouzarides.  Histone acetylases and deacetylases in cell proliferation. , 1999, Current opinion in genetics & development.

[13]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[14]  C. Benz,et al.  Clinical development of histone deacetylase inhibitors as anticancer agents. , 2005, Annual review of pharmacology and toxicology.

[15]  E. Sausville,et al.  Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  S. Schreiber,et al.  Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs. , 1997, Current opinion in chemical biology.

[17]  Robert Brown,et al.  A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors , 2008, Clinical Cancer Research.

[18]  K. Bhalla,et al.  A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies , 2006, Clinical Cancer Research.

[19]  L. Schwartz,et al.  Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  A. Kalita,et al.  4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[21]  A. Kalita,et al.  (2-amino-phenyl)-amides of omega-substituted alkanoic acids as new histone deacetylase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[22]  Design and synthesis of a novel class of histone deacetylase inhibitors. , 2001, Bioorganic & medicinal chemistry letters.

[23]  C. Maroun,et al.  Histone deacetylase inhibitors: latest developments, trends and prospects. , 2005, Current medicinal chemistry. Anti-cancer agents.

[24]  Z. Cao,et al.  CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo , 2006, Molecular Cancer Therapeutics.

[25]  Daniel Delorme,et al.  Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors. , 2002, Journal of medicinal chemistry.

[26]  M. Janicot,et al.  A first-in-man phase I study of R306465, a histone deacetylase (HDAC) inhibitor exploring pharmacokinetics (PK) and pharmacodynamics (PD) utilizing an electrochemiluminescent immunoassay in patients (p) with advanced tumours , 2007 .

[27]  Sylvain Lefebvre,et al.  MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo , 2008, Molecular Cancer Therapeutics.

[28]  P. Finn,et al.  Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. , 2003, Molecular cancer therapeutics.