Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

[1]  Shanghai Yu,et al.  SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. , 2014, Cancer research.

[2]  Daqing Sun,et al.  Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. , 2014, Journal of medicinal chemistry.

[3]  J. Canon,et al.  Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres. , 2014, Journal of medicinal chemistry.

[4]  Y. Wang,et al.  Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. , 2014, Journal of medicinal chemistry.

[5]  Jing Zhang,et al.  Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. , 2013, Journal of medicinal chemistry.

[6]  Xin Huang,et al.  Rational design and binding mode duality of MDM2-p53 inhibitors. , 2013, Journal of medicinal chemistry.

[7]  C. García-echeverría,et al.  Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic. , 2013, Bioorganic & medicinal chemistry letters.

[8]  Binh Vu,et al.  Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. , 2013, ACS medicinal chemistry letters.

[9]  J. Medina,et al.  An expeditious synthesis of the MDM2-p53 inhibitor AM-8553. , 2012, Journal of the American Chemical Society.

[10]  J. Canon,et al.  Structure-based design of novel inhibitors of the MDM2-p53 interaction. , 2012, Journal of medicinal chemistry.

[11]  Shanghai Yu,et al.  Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. , 2009, Journal of medicinal chemistry.

[12]  Alexei Vazquez,et al.  The genetics of the p53 pathway, apoptosis and cancer therapy , 2008, Nature Reviews Drug Discovery.

[13]  Dajun Yang,et al.  Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition , 2008, Proceedings of the National Academy of Sciences.

[14]  M. Kastan.  Wild-Type p53: Tumors Can't Stand It , 2007, Cell.

[15]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[16]  Carlos Cordon-Cardo,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2007, Nature.

[17]  Gerard I. Evan,et al.  Modeling the Therapeutic Efficacy of p53 Restoration in Tumors , 2006, Cell.

[18]  Su Qiu,et al.  Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. , 2006, Journal of medicinal chemistry.

[19]  L. Vassilev.  p53 Activation by small molecules: application in oncology. , 2005, Journal of medicinal chemistry.

[20]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[21]  P. Chène.  Inhibiting the p53–MDM2 interaction: an important target for cancer therapy , 2003, Nature Reviews Cancer.

[22]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[23]  A. Levine,et al.  Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Levine,et al.  Nuclear Export Is Required for Degradation of Endogenous p53 by MDM2 and Human Papillomavirus E6 , 1998, Molecular and Cellular Biology.

[25]  A. Levine,et al.  Nucleo‐cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein , 1998, The EMBO journal.

[26]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[27]  M. Kubbutat,et al.  Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability , 1997, Molecular and cellular biology.

[28]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[29]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[30]  Bert Vogelstein,et al.  Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 , 1993, Nature.

[31]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.