Imatinib (gleevec) revolutionized treatment of CML. After years of response, a patient develops resistance. Dasatinib overcomes most imatinib resistance mutations except T315I (gatekeeper mutation). Why does the T315I mutation confer resistance to both imatinib and first-generation TKIs but not ponatinib?
- A T315I substitution eliminates a critical threonine hydrogen bond and creates steric hindrance, blocking imatinib binding; ponatinib has a carbon-carbon triple bond allowing accommodation around the isoleucine residue ✓
- B T315I activates a survival kinase that phosphorylates and degrades imatinib before it reaches BCR-ABL
- C Ponatinib is a prodrug activated by BCR-ABL kinase itself, making T315I an activating mutation for ponatinib
- D T315I mutation creates a new hydrophobic pocket that ponatinib's larger molecular structure fills preferentially
Correct answer: A. T315I substitution eliminates a critical threonine hydrogen bond and creates steric hindrance, blocking imatinib binding; ponatinib has a carbon-carbon triple bond allowing accommodation around the isoleucine residue
Explanation
Threonine-315 in ABL kinase forms a critical hydrogen bond with imatinib, nilotinib, and dasatinib; the T315I substitution replaces this threonine with isoleucine, eliminating the hydrogen bond donor and creating a bulkier hydrophobic side chain that sterically clashes with these inhibitors. Ponatinib (AP24534) was specifically designed with a carbon-carbon triple bond linker that avoids this steric clash, allowing it to bind T315I-BCR-ABL. This makes ponatinib the drug of choice for T315I-mutated CML.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.