Definition

A targeted protein degrader (TPD) of the oncogenic KRAS substitution mutation G12D, using the proteolysis targeting chimera (PROTAC) technology, with potential antineoplastic activity. ASP3082 is comprised of an E3 ubiquitin ligase-binding moiety conjugated, via a linker, to a KRAS G12D-binding moiety. Upon administration, KRAS G12D degrader ASP3082 specifically targets and binds, with its KRAS G12D-targeting moiety, to KRAS G12D mutated protein and, with its E3 ligase-binding moiety, to the E3 ubiquitin ligase, thereby forming a ternary complex. This induces E3 ligase ubiquitination and proteasome-mediated degradation of KRAS G12D mutated protein. This prevents KRAS G12D-mediated signaling and activation of downstream survival pathways. This leads to an inhibition of the growth of tumor cells that overexpress KRAS G12D. 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.