A small molecule that inhibits RAS protein interactions offers hope for targeting this elusive protein.1
More than 30% of human cancers have mutated RAS, so it is one of the most sought-after cancer targets for drug developers, but the mutant RAS protein lacks drug-binding pockets. RAS genes include HRAS, KRAS, and NRAS, and these are frequently mutated in many of the most common and lethal tumors, including cancers of the pancreas, lung, and colon. Little progress has occurred on systemically targeting the RAS oncogenes, resulting in RAS being labeled as an undruggable cancer gene.
A team of scientists at the Icahn School of Medicine, The Scripps Cancer Research Institute, Albert Einstein College of Medicine, and the New York Structural Biology Center led by Premkumar Reddy, PhD, identified the first small molecule that can simultaneously inhibit the different signaling pathways activated by RAS oncogenes.
The small molecule is known as rigosertib or ON01910.Na. It inhibits interactions between proteins to prevent binding between RAS and signaling proteins (including RAF, PI3K and others) that turn a cell into a cancer cell. Structural experiments by the research team confirmed the mode of action for rigosertib and also demonstrated the potential for this targeted mechanism in the treatment of several RAS-driven cancers.
“This discovery is a significant breakthrough for the cancer field,” said Reddy, a professor of oncological sciences at the Icahn School of Medicine at Mount Sinai.
“Rigosertib’s mechanism of action represents a new paradigm for attacking the intractable RAS oncogenes. Our current focus is to use the information from our studies with rigosertib to design the next generation of small molecule RAS-targeting therapies, and we are excited to have recently identified several compounds which we think improve on the qualities of rigosertib.”
This drug is currently in phase III clinical trials at multiple sites, including Mount Sinai, for the treatment of myelodysplastic syndrome (MDS). Notably, rigosertib failed to demonstrate an improvement in overall survival compared with best supportive care in a previous phase III study reported in 2014 for patients with MDS who had failed, progressed, or relapsed on hypomethylating agents.
1. Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell. 2016;165(3):643-655. doi:10.1016/j.cell.2016.03.045.