Imatinib revolutionised the treatment of CML. Its primary mechanism involves:
- A Degradation of BCR-ABL oncoprotein via the ubiquitin-proteasome pathway by acting as a molecular glue
- B Competitive inhibition of the SH2 domain of BCR-ABL, preventing docking with downstream signalling proteins
- C Inhibition of BCR-ABL tyrosine kinase by occupying the ATP-binding site in the inactive conformation, preventing substrate phosphorylation ✓
- D Inhibition of PDGFR and c-KIT tyrosine kinases only, with no direct BCR-ABL inhibitory activity
Correct answer: C. Inhibition of BCR-ABL tyrosine kinase by occupying the ATP-binding site in the inactive conformation, preventing substrate phosphorylation
Explanation
Imatinib (Gleevec) is a Type II kinase inhibitor that inserts into the ATP-binding cleft of BCR-ABL when the kinase is in its inactive DFG-out conformation. By blocking ATP binding, it prevents autophosphorylation and substrate phosphorylation, shutting down constitutive tyrosine kinase signalling that drives CML proliferation. It also inhibits PDGFR and c-KIT (used in GIST), but its primary therapeutic target in CML is BCR-ABL.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.