Structure–activity relationships of KRAS-G12D inhibitors for pancreatic cancer

KRAS encodes a GTPase (Kirsten rat sarcoma viral oncogene homolog) crucial for cellular signal transduction, impacting proliferation, survival, and differentiation. KRAS is also a crucial oncogene in the pathology of pancreatic ductal adenocarcinoma (PDAC), greatly influencing the development and progression of the cancer. Mutations in KRAS occur in ∼95% of patients with PDAC, which makes them the most prevalent mutations related to this disease. However, no marketed drugs inhibiting the KRASG12D mutation against pancreatic cancer are currently available. Thus, in this review, we highlight structure–activity relationship (SAR) studies targeting KRAS-G12D with small organic molecules under investigation against pancreatic cancer.