Abstract ND10: 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

Abstract

Abstract 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. We will describe our SAR investigations and findings for our preclinical tool compound, RMC-6272 (also known as RM-006) and for RMC-5552, our clinical candidate. We will demonstrate that mTORC1-selective bi-steric inhibitors show combinatorial activity with both KRASG12C(OFF) and KRASG12C(ON) inhibitors, in KRASG12C STK11deficient NSCLC models and can forestall resistance to KRASG12C inhibitor monotherapy. In addition, we will show single agent activity of bi-steric mTORC1 inhibitors in preclinical models of tumors bearing PI3K/mTOR pathway alterations as primary drivers, including PTEN-deficient glioblastoma multiforme, TSC1/2-deficient renal cystadenoma cancer, and hepatocellular cancers harboring mTOR-activating β-catenin mutations. RMC-5552, through reactivation of 4EBP1 and inhibition of cap-dependent translation, has the potential to benefit cancer patients with genetically-defined tumors with activating mutations in the RAS and PI3K/mTOR pathways both as a single agent or in combination with RAS inhibitors. Citation Format: G. Leslie Burnett. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND10.