RMC-5552 is a potent and selective inhibitor of mTORC1 that is designed to preserve the tumor suppressive activity of 4EBP1 without the undesired inhibition of mTORC2. This development candidate is currently advancing into Phase 1 monotherapy dose escalation studies.
The mTOR Complex 1 (mTORC1) is a central node within the mTOR signaling pathway and a critical regulator of metabolism, growth and proliferation within cells, including cancer cells. The abnormal activation of mTORC1, and subsequent inactivation of the tumor suppressor 4EBP1, is a mechanism that is frequently harnessed by cancer cells to gain a growth and proliferation advantage over normal cells. As such, selective inhibition of mTORC1 to prevent the phosphorylation and inactivation of 4EBP1 is viewed as a potential therapeutic strategy for several tumor types including breast cancer, glioblastoma and renal cell carcinoma, among others.
Efforts to develop active site inhibitors of mTOR kinase have proven unsuccessful to date due to the poor clinical tolerability of the compounds, which is believed to be at least partly attributable to concurrent inhibition of the mTORC2 complex and/or other kinases besides mTORC1.
Leveraging our proprietary innovation engine, we have developed a novel collection of potent and selective compounds targeting mTORC1 which offer the potential to preserve the tumor suppressive properties of 4EBP1 in cancers where the mTORC1 pathway is activated. These compounds are bi-steric inhibitors that selectively inhibit mTORC1 while minimizing or avoiding inhibition of mTORC2 and other kinases. We believe that this selectivity for mTORC1 positions our compounds as uniquely suitable for administration to cancer patients at doses capable of preserving the tumor suppressor effects of 4EBP1.
We have selected RMC-5552 as a development candidate from our collection of selective mTORC1 inhibitors. In preclinical studies, RMC-5552 exhibited compelling anti-tumor activity in models of breast cancer and significantly prolonged survival in a model of orthotopic glioblastoma multiforme. Based on these findings, we currently plan to advance RMC-5552 into Phase 1 monotherapy studies.