Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

  • ACS Med Chem Lett. 2013 Dec 29;5(2):124-7. doi: 10.1021/ml400359z.
Zhuming Zhang  1 ,  Xin-Jie Chu  1 ,  Jin-Jun Liu  1 ,  Qingjie Ding  1 ,  Jing Zhang  1 ,  David Bartkovitz  1 ,  Nan Jiang  1 ,  Prabha Karnachi  1 ,  Sung-Sau So  1 ,  Christian Tovar  1 ,  Zoran M Filipovic  1 ,  Brian Higgins  1 ,  Kelli Glenn  1 ,  Kathryn Packman  1 ,  Lyubomir Vassilev  1 ,  Bradford Graves  1
Affiliations
  • 1. Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
PMID: 24900784 DOI: 10.1021/ml400359z
Abstract

The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for Cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 Inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.

Keywords
MDM2; apoptosis; cancer; p53; small molecule; wild-type.
Products