Imatinib (Gleevec) revolutionised CML treatment. Its mechanism of action and the molecular target are:

• A Inhibits BCR-ABL tyrosine kinase by binding the ATP-binding pocket in its active (open) conformation, preventing ATP binding and substrate phosphorylation
• B Inhibits BCR-ABL by binding its inactive (closed) conformation, locking the kinase off; it also inhibits c-Kit and PDGFR ✓
• C Inhibits histone deacetylase (HDAC), silencing BCR-ABL transcription
• D Promotes ubiquitin-proteasome-mediated degradation of BCR-ABL fusion protein

Explanation

Imatinib is a type II tyrosine kinase inhibitor: it binds the inactive, DFG-out conformation of BCR-ABL, stabilising it in a closed/inactive state and preventing ATP binding. This mechanistic selectivity explains why the T315I 'gatekeeper' mutation (which prevents adopting the inactive conformation) causes imatinib resistance — ponatinib can overcome this. Imatinib also inhibits c-KIT (useful in GIST) and PDGFR. It does not affect HDAC or the proteasome pathway.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.