RMC-9805

Zoldonrasib is an orally bioavailable covalent tri-complex inhibitor of the oncogenic KRAS substitution mutation G12D, with potential antineoplastic activity. Upon oral administration, zoldonrasib specifically targets and non-covalently binds to cyclophilin A to form a non-covalent binary complex, which subsequently covalently and irreversibly binds to the active GTP-bound form of KRAS G12D (KRASG12D(ON)). This prevents KRAS G12D-mediated signaling and activation of downstream survival pathways. This causes apoptosis in KRAS G12D-expressing tumor cells. In addition, inhibition of KRAS G12D signaling by zoldonrasib abrogates the suppressive tumor microenvironment (TME) and enhances an anti-tumor immune response which further leads to an inhibition of proliferation of KRAS G12D-expressing tumor cells. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell proliferation, invasion, and metastasis.