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.
Subject(s)
Indoles/chemistry , Indolizidines/chemistry , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Spiro Compounds/chemistry , Apoptosis/drug effects , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Humans , Imidazolines/chemistry , Indoles/therapeutic use , Indoles/toxicity , Indolizidines/therapeutic use , Indolizidines/toxicity , Molecular Dynamics Simulation , Neoplasms/drug therapy , Protein Binding , Protein Structure, Tertiary , Proto-Oncogene Proteins c-mdm2/metabolism , Pyrrolidines/chemistry , Spiro Compounds/therapeutic use , Spiro Compounds/toxicity , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism , para-Aminobenzoates/chemistryABSTRACT
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.
ABSTRACT
Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
