Imatinib (Gleevec) resistance in CML most commonly develops through ABL kinase domain point mutations. The T315I ('gatekeeper') mutation confers resistance to imatinib, dasatinib, and nilotinib. Which third-generation BCR-ABL inhibitor was specifically developed to overcome T315I?

• A Bosutinib — a dual Src/ABL inhibitor with improved T315I coverage
• B Asciminib — an allosteric STAMP inhibitor that overcomes all gatekeeper mutations
• C Ponatinib — a pan-BCR-ABL inhibitor with a carbon-carbon triple bond that avoids steric clash with the mutated isoleucine at position 315 ✓
• D Bafetinib — a dual BCR-ABL/Lyn inhibitor approved for T315I in India

Explanation

The T315I mutation replaces threonine (with a hydroxyl group that forms a hydrogen bond with imatinib, dasatinib, and nilotinib) with bulky isoleucine, creating steric clash and abolishing hydrogen bonding with first- and second-generation TKIs. Ponatinib (AP24534) was rationally designed with a carbon-carbon triple bond linker (ethynyl group) that bypasses the steric obstruction imposed by the T315I isoleucine side chain, maintaining potent binding to the mutant ABL kinase. It is approved for T315I-mutant CML and Philadelphia chromosome-positive ALL. Asciminib targets the ABL myristate pocket allosterically (STAMP mechanism) and also covers T315I (asciminib STAMP combination), but ponatinib remains the established agent specifically developed for T315I.

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

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Written and medically reviewed by the StethoPrep medical team.