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

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 o...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2014-08, Vol.22 (15), p.4001-4009
Main Authors: Zhang, Zhuming, Ding, Qingjie, Liu, Jin-Jun, Zhang, Jing, Jiang, Nan, Chu, Xin-Jie, Bartkovitz, David, Luk, Kin-Chun, Janson, Cheryl, Tovar, Christian, Filipovic, Zoran M., Higgins, Brian, Glenn, Kelli, Packman, Kathryn, Vassilev, Lyubomir T., Graves, Bradford
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Binding Sites
Cancer
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
MDM2
Molecular Dynamics Simulation
Neoplasms - drug therapy
p53
para-Aminobenzoates - chemistry
Protein Binding
Protein Structure, Tertiary
Protein–protein interaction
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.05.072