Cyclopropane is the smallest cyclic compound with unique structural features and physicochemical properties, which is widely used in the design of small molecule drugs. In drug design, it is often used to increase activity, fix conformation and improve PK and water solubility. The introduction of cyclopropyl groups into drugs can change various properties of molecules, such as improving metabolic stability; increasing biological activity; enhancing drug efficacy; limiting polypeptide conformation and slowing down its hydrolysis; reducing plasma clearance; improving drug dissociation and many more. Cyclopropane rings are widely found in marketed drugs, including cardiovascular drugs, central nervous system (CNS) drugs, anticancer drugs, autoimmune and anti-inflammatory drugs.
Over 30% of all human cancers, including a certain percentage of pancreatic, colorectal, lung cancers, and AML are driven by mutations of RAS genes. There is a significant unmet medical need in RAS mutant cancers.
Revolution Medicines’ investigational drug, RMC-6236 is an oral, non-covalent, RAS (ON) inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. RMC-6236 is under clinical phase I studies as monotherapy in NSCLC and PDAC, and advanced solid tumors harboring KRAS G12X mutations.