Findings Published in the Journal of Medicinal Chemistry Demonstrate Compound’s Exceptional Selectivity for mTORC1 over mTORC2
REDWOOD CITY, Calif., Dec. 19, 2022
Revolution Medicines, Inc. 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.
Full Paper Here:
Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors
Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of “bi-steric inhibitors” that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRAS G12C mutant 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-5552 in the preclinical setting compared to earlier mTORC inhibitors provides a strong rationale for evaluating it in patients with tumors that have abnormally high mTORC1 growth signaling, including in combination with our RAS(ON) Inhibitors in patients with tumors that have both RAS and mTORC1 pathway co-mutations.”
The manuscript published in the Journal of Medicinal Chemistry is titled, “Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-activated Tumors,” and can be accessed at: https://doi.org/10.1021/acs.jmedchem.2c01658
The mTOR Complex 1 (mTORC1) is a central node within the mTOR signaling pathway and a critical regulator of metabolism, growth, and proliferation in cancer cells. Oncogenic mutations of genes encoding proteins that lie upstream of mTOR, including PI3K, PTEN, and STK11, can drive abnormal activation of mTORC1 and subsequent inactivation of the tumor suppressor 4EBP1. Selective inhibition of mTORC1 to reactivate 4EBP1 is a potential therapeutic strategy for patients with tumors bearing such mutations. These mutations are often co-occurring with RAS mutations in RAS-addicted tumors and combinations of mTORC1- and RAS-targeted inhibitors may be of particular benefit in this context.
About Revolution Medicines, Inc.
Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers.