molecules of the month


selective, bi-steric mTORC1 inhibitor

Ph. I/Ib for r/r solid tumors

opt. of rapalog + linker + mTOR inh.

J. Med. Chem., December 19, 2022

Revolution Medicines, Redwood City, CA

RMC-5552 chemical structure selective, bi-steric mTORC1 inhibitor - Revolution Medicines, Redwood City, CA
3 mins read

What is it? RMC-5552 is a potential first-in-class, bi-steric, mTOR1-selective inhibitor in Ph. I/IIb (NCT04774952, NCT05557292) as an IV agent to treat tumors with hyperactive mTORC1 signaling. This previously highlighted molecule is a bi-steric inhibitor containing an allosteric C32-hydroxy rapamycin derivative linked to an orthosteric, second-generation mTOR inhibitor, sapanisertib (MLN0128, INK128). Inspired by the first reported bi-steric mTOR inhibitor RapaLink-1 from the Shokat lab, RMC-5552 was optimized to have 40-fold selectivity for mTORC1 over mTORC2 to address adverse effects commonly associated with pan-mTOR inhibition. Why do we care? The phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the most pursued targets in cancer therapy, but many candidates have been withdrawn due to toxicity issues and…

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