Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hyperactivation of mTOR kinase is common in many cancers due to pathway mutations or crosstalk with drivers like RAS.
• Existing mTOR inhibitors (allosteric for mTORC1, dual for mTORC1/mTORC2) have shown limited clinical utility.
• There is a need for improved strategies to target the PI3K/mTOR pathway in cancer therapy.

Purpose of the Study:

• To develop a novel class of bi-steric inhibitors targeting the mechanistic target of rapamycin complex 1 (mTORC1).
• To evaluate the preclinical profile of RMC-5552 and RMC-6272 as selective mTORC1 inhibitors.
• To investigate the combination therapy of selective mTORC1 inhibition with KRAS^G12C inhibition in KRAS-mutant non-small cell lung cancer (NSCLC).

Main Methods:

• Design and synthesis of bi-steric inhibitors targeting both orthosteric and allosteric sites of mTORC1.
• Preclinical evaluation of RMC-5552 and RMC-6272 in relevant cancer models.
• Assessment of combination therapy efficacy in a preclinical model of KRAS^G12C-mutant NSCLC resistant to KRAS^G12C inhibitor monotherapy.

Main Results:

• Discovery and preclinical characterization of RMC-5552 and RMC-6272, novel bi-steric inhibitors with deep mTORC1 inhibition and selectivity over mTORC2.
• Demonstration of enhanced antitumor activity when selective mTORC1 inhibition is combined with covalent KRAS^G12C inhibition.
• Evidence of increased efficacy in a preclinical NSCLC model resistant to KRAS^G12C inhibitor monotherapy.

Conclusions:

• Bi-steric inhibitors represent a promising new class of drugs for targeting mTORC1.
• Selective mTORC1 inhibition combined with KRAS^G12C inhibition offers a potential therapeutic strategy for resistant KRAS-mutant NSCLC.
• Further clinical development of these novel inhibitors is warranted.