Imatinib resistance in CML arising from the BCR-ABL T315I (gatekeeper) mutation is best treated with:

• A Dasatinib — a dual Src/ABL inhibitor with broader binding pocket access than imatinib
• B Ponatinib — a 3rd-generation TKI designed with a carbon-carbon triple bond that circumvents the steric hindrance of the T315I isoleucine substitution ✓
• C Nilotinib — higher affinity for BCR-ABL with reduced steric clash at the ATP-binding site
• D Bosutinib — minimal binding site interaction with residue 315, avoiding resistance

Explanation

T315I is the 'gatekeeper' mutation in BCR-ABL where threonine 315 is replaced by bulkier isoleucine, removing a critical hydrogen bond contact and causing steric clash with imatinib, dasatinib, and nilotinib — all of which require contact with or proximity to residue 315. Ponatinib (AP24534) was rationally designed with a carbon-carbon triple bond linker (alkynyl group) that is slender enough to bypass the isoleucine side chain without steric conflict, maintaining binding. This makes ponatinib the only approved TKI active against T315I. However, ponatinib carries a risk of arterial thrombosis and vascular occlusion, limiting its use. Asciminib (STAMP inhibitor targeting myristoyl pocket) is also T315I-active.

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

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Written and medically reviewed by the StethoPrep medical team.