Imatinib is a BCR-ABL tyrosine kinase inhibitor. The T315I mutation ('gatekeeper mutation') in BCR-ABL causes resistance because:
- A Threonine to isoleucine substitution removes a hydrogen bond contact between imatinib and the ATP binding pocket and adds steric hindrance ✓
- B Isoleucine at position 315 activates ABL kinase constitutively, bypassing imatinib's inhibitory binding site
- C T315I mutation causes BCR-ABL to lose its kinase activity and shift to a novel signalling pathway
- D T315I reduces BCR-ABL expression, requiring higher imatinib concentrations beyond achievable plasma levels
Correct answer: A. Threonine to isoleucine substitution removes a hydrogen bond contact between imatinib and the ATP binding pocket and adds steric hindrance
Explanation
Threonine at position 315 in BCR-ABL normally forms a critical hydrogen bond with the hydroxyl group of imatinib, and its small side chain allows key hydrophobic contacts within the ATP-binding pocket. The T315I mutation replaces threonine with the bulkier, hydrophobic isoleucine, which (1) eliminates the hydrogen bond contact, and (2) sterically clashes with imatinib, dasatinib, and nilotinib. Ponatinib (third-generation TKI) was specifically designed with a carbon-carbon triple bond at C3 to accommodate the isoleucine and overcome T315I resistance.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.