3OXZ

Crystal structure of ABL kinase domain bound with a DFG-out inhibitor AP24534

Summary for 3OXZ

• Entry DOI: 10.2210/pdb3oxz/pdb
• Related: 3IK3 3OY3
• Descriptor: Tyrosine-protein kinase ABL1, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide (3 entities in total)
• Functional Keywords: protein-inhibitor complex, protein kinase two-domain fold, phosphotransferase, atp binding, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (mouse)
• Cellular location: Cytoplasm, cytoskeleton: P00520
• Total number of polymer chains: 1
• Total formula weight: 33330.00

Authors

Zhou, T.,Huang, W.S.,Wang, Y.,Thomas, M.,Keats, J.,Xu, Q.,Rivera, V.,Shakespeare, W.C.,Clackson, T.,Dalgarno, D.C.,Zhu, X. (deposition date: 2010-09-22, release date: 2010-12-15, Last modification date: 2023-09-06)

Primary citation

Zhou, T.,Commodore, L.,Huang, W.S.,Wang, Y.,Thomas, M.,Keats, J.,Xu, Q.,Rivera, V.M.,Shakespeare, W.C.,Clackson, T.,Dalgarno, D.C.,Zhu, X.
Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance.
Chem.Biol.Drug Des., 77:1-11, 2011

PubMed Abstract: 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.

PubMed: 21118377
DOI: 10.1111/j.1747-0285.2010.01054.x

Experimental method

X-RAY DIFFRACTION (2.2 Å)