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

2013; American Chemical Society; Volume: 5; Issue: 2 Linguagem: Inglês

10.1021/ml400359z

1948-5875

Zhuming Zhang, Xin‐Jie Chu, Jinjun Liu, Qingjie Ding, Jing Zhang, David Bartkovitz, Nan Jiang, Prabha Karnachi, Sung‐Sau So, Christian Tovar, Zoran Filipovic, Brian Higgins, Kelli Glenn, Kathryn Packman, Lyubomir T. Vassilev, Bradford Graves,

Microtubule and mitosis dynamics

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.