Business
Revolution Medicines Announces Publication Describing Design and Synthesis of RMC-5552, a First-in-Class, Bi-Steric mTORC1-Selective Inhibitor
Findings Published in the Journal of Medicinal Chemistry Demonstrate Compound’s Exceptional Selectivity for mTORC1 over mTORC2 Tumor Regressions Observed
About this update from Revolution Medicines, Inc.
[{"type":"text","content":"Findings Published in the Journal of Medicinal Chemistry Demonstrate Compound’s Exceptional Selectivity for mTORC1 over mTORC2 Tumor Regressions Observed During Combination Treatment with a Bi-Steric mTORC1-Selective Inhibitor and a KRASG12C-Selective Inhibitor in Preclinical Lung Cancer Model that is Resistant to KRASG12C Inhibitor Monotherapy REDWOOD CITY, Calif., Dec. 19, 2022 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, today announced publication of a manuscript in the Journal of Medicinal Chemistry that details the discovery efforts leading to RMC-5552, the company’s first-in-class, bi-steric mTORC1-selective inhibitor. The manuscript describes the unprecedented compound profile that includes 40-fold selectivity for mTORC1 over mTORC2 and greater than 53-fold selectivity over other lipid kinases. The paper also shows that selective mTORC1 inhibition using the company’s related preclinical tool compound (RMC-6272) in combination with a covalent KRASG12C inhibitor induced tumor regressions in a preclinical model of KRASG12C mutant non-small cell lung cancer (NSCLC) that exhibits resistance to KRASG12C inhibitor monotherapy. RMC-5552 is designed to suppress phosphorylation and inactivation of 4EBP1, a key translational regulator of oncogene expression, in cancers with hyperactive mTORC1 signaling. This bi-steric compound is designed to bind simultaneously to two different sites on mTORC1 to drive deep inhibition of mTORC1 while maintaining selectivity for mTORC1 over mTORC2, a unique profile compared to prior generations of mTOR inhibitors. Revolution Medicines is currently evaluating RMC-5552 as monotherapy in a Phase 1/1b clinical trial in patients with refractory solid tumors (NCT04774952), and initial antitumor activity has been reported. The company plans to evaluate RMC-5552 in combination with RAS(ON) inhibitors in patients with cancers harboring mutations in both RAS and the mTOR pathways. “The Journal of Medicinal Chemistry manuscript details the sophisticated structure-based chemical design and synthesis employed by our drug discovery team that produced RMC-5552,” said Steve Kelsey, M.D., president, research and development at Revolution Medicines. “The differentiated antitumor and tolerability profile of RMC-...