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

Zhuming Zhang; Qingjie Ding; Jin-Jun Liu; Jing Zhang; Nan Jiang; Xin-Jie Chu; David Bartkovitz; Kin-Chun Luk; Cheryl Janson; Christian Tovar; Zoran M Filipovic; Brian Higgins; Kelli Glenn; Kathryn Packman; Lyubomir T Vassilev; Bradford Graves

doi:10.1016/j.bmc.2014.05.072

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. Epub 2014 Jun 11.

Authors

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.

MeSH terms

Apoptosis / drug effects
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Humans
Imidazolines / chemistry
Indoles / chemistry*
Indoles / therapeutic use
Indoles / toxicity
Indolizidines / chemistry*
Indolizidines / therapeutic use
Indolizidines / toxicity
Molecular Dynamics Simulation
Neoplasms / drug therapy
Protein Binding
Protein Structure, Tertiary
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Pyrrolidines / chemistry
Spiro Compounds / chemistry*
Spiro Compounds / therapeutic use
Spiro Compounds / toxicity
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / metabolism
para-Aminobenzoates / chemistry

Substances

Imidazolines
Indoles
Indolizidines
Pyrrolidines
RG7112
RG7388
RO8994
Spiro Compounds
Tumor Suppressor Protein p53
para-Aminobenzoates
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2