A 25-year-old woman is diagnosed with chronic myeloid leukemia (CML). Cytogenetics reveals the Philadelphia chromosome — a reciprocal translocation between chromosomes 9 and 22, creating the BCR-ABL fusion gene. The resulting chimeric oncoprotein has constitutively active tyrosine kinase activity. Imatinib blocks this kinase. At the molecular level, imatinib is best classified as which type of inhibitor?

• A An irreversible competitive inhibitor that covalently modifies the ATP-binding site
• B A non-competitive allosteric inhibitor that stabilizes the inactive conformation of the kinase
• C An antisense oligonucleotide that blocks BCR-ABL mRNA translation
• D A reversible competitive inhibitor that occupies the ATP-binding pocket of BCR-ABL kinase, blocking substrate phosphorylation ✓

Explanation

Imatinib (Gleevec) is a reversible competitive inhibitor that binds the ATP-binding pocket of BCR-ABL tyrosine kinase in its inactive conformation, preventing ATP from binding and thereby blocking phosphorylation of downstream substrates. It competes with ATP for the same binding site. Its specificity for the inactive kinase conformation explains its selectivity over normal ABL and other kinases.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.