Imatinib revolutionized treatment of CML. Its mechanism of selective toxicity to CML cells involves:
- A Inhibiting PDGF receptor kinase as its primary mechanism in CML cells
- B Inducing apoptosis of CML cells through direct p53 pathway activation
- C Binding the ATP-binding pocket of BCR-ABL tyrosine kinase in its inactive conformation, preventing substrate phosphorylation ✓
- D Cross-linking BCR-ABL DNA domains preventing transcription of the fusion oncogene
Correct answer: C. Binding the ATP-binding pocket of BCR-ABL tyrosine kinase in its inactive conformation, preventing substrate phosphorylation
Explanation
Imatinib competitively binds the ATP-binding cleft of BCR-ABL tyrosine kinase when the kinase is in its inactive (DFG-out) conformation, preventing ATP binding and thus substrate tyrosine phosphorylation. BCR-ABL is constitutively active in CML (due to t(9;22) translocation) and drives uncontrolled proliferation. Normal ABL kinase spends most of its time in this inactive state and is not constitutively active, contributing to selectivity. Resistance develops through point mutations in the kinase domain (e.g., T315I gatekeeper mutation).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.