A patient with CML on imatinib develops resistance due to T315I 'gatekeeper' mutation. Which drug overcomes this specific mutation, and why does T315I confer resistance to imatinib, dasatinib, and nilotinib?

• A Ponatinib (AP24534) — the T315I substitution replaces a threonine whose hydroxyl group forms a critical hydrogen bond with imatinib/dasatinib/nilotinib; replacing threonine with isoleucine (T315I) eliminates this bond and adds steric bulk blocking their binding; ponatinib's ethynyl group accommodates the mutant residue ✓
• B Bosutinib — T315I mutation activates BCR-ABL constitutively to a conformation not recognised by earlier inhibitors, and bosutinib selectively recognises this activated conformation
• C Asciminib — allosteric STAMP inhibitor targeting the myristoyl pocket that is unaffected by kinase domain mutations including T315I
• D Homoharringtonine — non-targeted protein synthesis inhibitor that kills CML cells regardless of BCR-ABL mutation status

Explanation

The T315I 'gatekeeper' mutation in BCR-ABL converts threonine-315 to isoleucine. The threonine-315 hydroxyl group forms a direct hydrogen bond with all first- and second-generation BCR-ABL inhibitors (imatinib, dasatinib, nilotinib, bosutinib). The isoleucine substitution eliminates this hydrogen bond and introduces steric hindrance (isoleucine's methyl group clashes with the binding pose of these drugs). Ponatinib's design incorporates a carbon-carbon triple bond (ethynyl linker) that fits into the space created by the T315I mutation while making alternative van der Waals contacts. However, asciminib (option C) is also now approved for T315I via its STAMP mechanism; the question asks which drug overcomes T315I by accommodating the structural change, which precisely describes ponatinib's design rationale.

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

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Written and medically reviewed by the StethoPrep medical team.