Imatinib (a first-generation TKI) is used in CML. Its mechanism and the basis of resistance via T315I mutation are:

• A Imatinib activates BCR-ABL's GTPase, promoting tumor differentiation; T315I mutation constitutively activates the kinase
• B Imatinib inhibits protein degradation via proteasome blockade; T315I activates the 26S proteasome
• C Imatinib is an allosteric inhibitor at the substrate-binding site; T315I alters substrate specificity
• D Imatinib inhibits BCR-ABL by binding the ATP-binding site when the kinase is in inactive conformation; T315I (gatekeeper) mutation blocks imatinib binding while preserving ATP binding ✓

Explanation

Imatinib occupies the ATP-binding pocket of BCR-ABL when the kinase adopts its inactive (DFG-out) conformation, blocking substrate phosphorylation; the T315I mutation replaces a critical threonine 'gatekeeper' residue with a bulky isoleucine, removing a hydrogen bond contact and creating steric clash with imatinib/dasatinib/nilotinib while allowing ATP to bind normally. Ponatinib and asciminib are active against T315I: ponatinib accommodates the mutation; asciminib binds the myristoyl pocket (allosteric site), bypassing the ATP-site entirely.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.