2. Academic Validation
  3. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

  • Bioorg Med Chem. 2014 Aug 1;22(15):4001-9. doi: 10.1016/j.bmc.2014.05.072.
Zhuming Zhang 1,  Qingjie Ding 2,  Jin-Jun Liu 2,  Jing Zhang 2,  Nan Jiang 2,  Xin-Jie Chu 2,  David Bartkovitz 2,  Kin-Chun Luk 2,  Cheryl Janson 3,  Christian Tovar 4,  Zoran M Filipovic 4,  Brian Higgins 4,  Kelli Glenn 5,  Kathryn Packman 4,  Lyubomir T Vassilev 4,  Bradford Graves 6
Affiliations

Affiliations

  • 1 Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: zzhang85@its.jnj.com.
  • 2 Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
  • 3 Discovery Technologies, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
  • 4 Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
  • 5 Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States.
  • 6 Discovery Technologies, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: bjgraves101@gmail.com.
PMID: 24997575 DOI: 10.1016/j.bmc.2014.05.072
Abstract

The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.

Keywords

Apoptosis; Cancer; MDM2; Protein–protein interaction; p53.

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