Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

Journal Article · Fri Jan 20 04:00:00 EST 2012 · Chem. Biol. Drug Des.

DOI:https://doi.org/10.1111/j.1747-0285.2010.01054.x· OSTI ID:1026547

Zhou, Tianjun; Commodore, Lois; Huang, Wei-Sheng; Wang, Yihan; Thomas, Mathew; Keats, Jeff; Xu, Qihong; Rivera, Victor M; Shakespeare, William C; Clackson, Tim; Dalgarno, David C; Zhu, Xiaotian ^[1]

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1. ARIAD

The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive network of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1026547
• Journal Information: Chem. Biol. Drug Des., Journal Name: Chem. Biol. Drug Des. Journal Issue: (1) ; 01, 2011 Vol. 77; ISSN 1747-0277
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ANTINEOPLASTIC DRUGS
ENZYME INHIBITORS
GENE MUTATIONS
MUTANTS
MUTATIONS
MYELOID LEUKEMIA
PHOSPHOTRANSFERASES
RESIDUES
STRUCTURE-ACTIVITY RELATIONSHIPS
TYROSINE