Imatinib (STI-571) revolutionized CML treatment. After decades of use, patients on imatinib occasionally develop resistance. The most common mutation causing imatinib resistance in BCR-ABL positive CML is the T315I 'gatekeeper' mutation. What third-generation TKI specifically overcomes this mutation?

• A Nilotinib — second-generation TKI with improved binding to T315I mutant ABL kinase
• B Dasatinib — dual Src/ABL inhibitor that avoids steric clash at the gatekeeper position
• C Bosutinib — third-generation TKI that induces autophagic degradation of T315I mutant BCR-ABL protein
• D Ponatinib — third-generation TKI designed with a carbon-carbon triple bond that bypasses the bulky isoleucine at the gatekeeper position via non-traditional binding ✓

Explanation

The T315I ('gatekeeper') mutation replaces threonine-315 with isoleucine in the ABL kinase domain. Threonine-315 normally makes a critical hydrogen bond with imatinib. The T315I substitution eliminates this H-bond and introduces a bulky hydrophobic isoleucine that creates steric clash preventing imatinib (and most second-generation TKIs like nilotinib, dasatinib, bosutinib) from binding effectively. Ponatinib (AP24534) is a third-generation BCR-ABL TKI specifically engineered with a carbon-carbon ethynyl (triple bond) linkage in its structure that bypasses the bulky T315I gatekeeper residue without steric clash, allowing it to maintain contact with other key binding residues and inhibit both wild-type and T315I mutant ABL. It is also active against 32 of 33 tested BCR-ABL mutations. Asciminib (STAMP inhibitor) is another agent that overcomes T315I by binding the ABL myristoyl pocket (allosteric site) rather than the ATP-binding site.

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

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Written and medically reviewed by the StethoPrep medical team.