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
  • 1. Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. Electronic address: [email protected].
  • 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: [email protected].
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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