Abstract B55: Antitumor activity of the MDM2 antagonist RG7388.

Abstract

Abstract The p53 tumor suppressor is a transcription factor that inhibits tumor development by inducing cell cycle arrest or apoptosis in response to diverse stresses. In normal cells, p53 levels are tightly controlled by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 is overproduced in many human cancers, thereby impairing p53 function. Antagonists of p53-MDM2 interaction can reactivate p53 and offer a novel approach to cancer therapy. The first potent and selective small-molecule inhibitors of p53-MDM2 binding, the nutlins, provided preclinical proof-of-concept for MDM2 antagonists as therapeutics for patients with tumors expressing wild-type p53. Subsequently, a member of the nutlin family, RG7112, was the first small molecule inhibitor of MDM2 to be tested clinically. Here we describe, RG7388, a highly optimized agent with analogous mechanism of action representing an entirely new branch of the nutlin family of MDM2 antagonists. Like RG7112, RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule, effectively displacing p53 from MDM2, and leading to p53 stabilization and activation of the p53 pathway. However, RG7388 is derived from a distinct chemical series that binds with higher potency and selectivity to the MDM2 protein. RG7388 has substantially improved pharmacological properties, resulting in superior preclinical efficacy at lower doses and exposures as compared with its predecessor, RG7112. RG7388 elicits growth arrest and apoptosis at approximately 10-fold lower concentrations in vitro and in vivo, has an improved CYP inhibition profile, and a 2.5- to 20-fold lower projected human efficacious dose as compared with RG7112. Tumors with functional p53 signaling and MDM2 over-expression or amplification are likely to be the most sensitive to RG7388, however preclinical studies indicate that tumors with normal MDM2 levels may also respond to this novel therapeutic strategy. Results from preclinical safety and toxicology studies support further exploration of this compound in cancer patients. RG7388 is a promising agent that may offer a new therapeutic option and is currently in clinical testing in both solid and hematologic malignancies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B55. Citation Format: Brian Higgins, Christian Tovar, Kelli Glenn, Antje Walz, Zoran Filipovic, Yu-E Zhang, Markus Dangl, Bradford Graves, Lyubomir Vassilev, Kathryn Packman. Antitumor activity of the MDM2 antagonist RG7388. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B55.