Imatinib mesylate revolutionised the treatment of CML. Its molecular target is the BCR-ABL tyrosine kinase. The mechanism by which imatinib specifically inhibits BCR-ABL is:

• A Covalent irreversible binding to the ATP-binding site of BCR-ABL, permanently inactivating the kinase
• B Competitive binding to the ATP-binding pocket of BCR-ABL in its inactive conformation, blocking substrate phosphorylation and preventing proliferative signalling ✓
• C Binding to the substrate recognition domain of BCR-ABL, preventing CrkL and STAT5 docking
• D Inhibition of proteasomal degradation of BCR-ABL, trapping it in a non-functional conformation

Explanation

Imatinib binds competitively and reversibly to the ATP-binding cleft of BCR-ABL kinase, stabilising the inactive (DFG-out) conformation of the kinase domain. In this conformation, the DFG motif is shifted and the activation loop occludes the substrate binding site, preventing ATP binding and phosphorylation of downstream signalling proteins. The binding is competitive with ATP but is not covalent/irreversible (unlike osimertinib for EGFR). Second-generation BCR-ABL inhibitors (dasatinib, nilotinib) bind with higher affinity and overcome many imatinib-resistant mutations except 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.