Protein Kinase Inhibitors in Cancer Chemotherapy

Introduction & rationale

• Pathway-targeted (molecularly targeted) anticancer drugs — block specific oncogenic molecular lesions that drive the cancer, unlike classic cytotoxics that hit DNA/mitosis non-selectively; they exploit driver mutations the tumour is "addicted" to (oncogene addiction), giving a wider therapeutic window and a target-mapped (not generic-myelosuppressive) toxicity profile.
• Protein kinase inhibitors (PKIs) — small molecules (<1 kDa) that enter cells and engage an intracellular kinase target (usually the ATP-binding pocket); oral, hepatic-CYP metabolised, often inhibit multiple kinases. Contrast with monoclonal antibodies (~150 kDa, extracellular, parenteral).
• Prototype & landmark — imatinib (Gleevec, 2001) against BCR-ABL in CML was the first PKI designed against a cancer driver mutation to gain FDA approval — the paradigm of targeted therapy and a WHO essential medicine.
• USAN stem signals the target — -tinib = tyrosine kinase (erlotinib); -anib = angiogenesis (pazopanib); -ciclib = CDK4/6 (palbociclib); -rafenib = BRAF (vemurafenib); -lisib = PI3K; -parib = PARP (olaparib); -zomib = proteasome (bortezomib).