The PI3K/mTOR and RAS signaling pathways are hyperactivated in a wide range of human cancers. Several points of cross-talk and intersecting feedback mechanisms have been described and activation of mTOR signaling frequently mediates escape from RAS pathway inhibition. Revolution Medicines has developed a novel class of selective mTORC1 inhibitors, termed ‘bi-steric inhibitors’, that interact with both the ATP- and FKBP12/FRB-binding sites of mTORC1. These compounds potently and selectively inhibit mTORC1 over mTORC2 and other lipid kinases. Unlike rapalogs, such as everolimus, these bi-steric inhibitors suppress 4EBP1 phosphorylation in vivo and induce growth suppression and apoptosis in various genetically-defined preclinical models of human cancer. Here we describe the discovery and preclinical profile of our development candidate, RMC-5552, as well as our in vivo tool compound, RMC-6272. By leveraging our beyond rule of five drug discovery paradigm and modular synthesis approach, alongside computational and crystallographic insights, we have developed a series of bi-steric compounds derived from rapamycin that are selective and have sub-nanomolar phospho-4EBP1 inhibitory potency. We also demonstrate that our mTORC1-selective bi-steric inhibitors show combinatorial activity with KRASG12C(OFF) inhibitors and can forestall resistance to KRASG12C inhibitor monotherapy in preclinical models of KRASG12C STK11deficient NSCLC.

Discovery of RMC-5552, a selective bi-steric inhibitor of mTORC1 that suppresses 4EBP1 phosphorylation, for the treatment of mTORC1-activated tumors including RAS pathway escape

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.