Imatinib, a tyrosine kinase inhibitor, achieves selectivity for the BCR-ABL oncoprotein (in CML) by:

• A Intercalating into the fusion gene's DNA, preventing transcription of BCR-ABL
• B Binding the inactive conformation of BCR-ABL kinase domain, occupying the ATP-binding pocket and preventing substrate phosphorylation ✓
• C Activating the BCR-ABL proteasomal degradation pathway via ubiquitination
• D Blocking the SH2 domain of BCR-ABL, preventing docking of downstream signalling molecules

Explanation

Imatinib (STI-571) binds specifically to the inactive DFG-out conformation of the BCR-ABL kinase domain, occupying the adenosine (ATP) binding pocket. This prevents ATP binding and thereby inhibits the tyrosine kinase activity that drives CML cell proliferation. It also inhibits c-KIT (GIST) and PDGFR by the same mechanism. The DFG-out binding explains some selectivity but also susceptibility to resistance mutations like T315I (the 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.