3IK3

AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance

Summary for 3IK3

• Entry DOI: 10.2210/pdb3ik3/pdb
• Descriptor: Proto-oncogene 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: bcr-abl, cml, t315i, inhibitor, mutation, drug resistance, alternative splicing, atp-binding, cell adhesion, chromosomal rearrangement, cytoplasm, cytoskeleton, kinase, lipoprotein, magnesium, manganese, metal-binding, myristate, nucleotide-binding, nucleus, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase
• Biological source: Mus musculus (mouse)
• Cellular location: Cytoplasm, cytoskeleton: P00520
• Total number of polymer chains: 2
• Total formula weight: 67573.16

Authors

Zhou, T. (deposition date: 2009-08-05, release date: 2009-11-03, Last modification date: 2023-09-06)

Primary citation

O'Hare, T.,Shakespeare, W.C.,Zhu, X.,Eide, C.A.,Rivera, V.M.,Wang, F.,Adrian, L.T.,Zhou, T.,Huang, W.S.,Xu, Q.,Metcalf, C.A.,Tyner, J.W.,Loriaux, M.M.,Corbin, A.S.,Wardwell, S.,Ning, Y.,Keats, J.A.,Wang, Y.,Sundaramoorthi, R.,Thomas, M.,Zhou, D.,Snodgrass, J.,Commodore, L.,Sawyer, T.K.,Dalgarno, D.C.,Deininger, M.W.,Druker, B.J.,Clackson, T.
AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.
Cancer Cell, 16:401-412, 2009

PubMed Abstract: Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.

PubMed: 19878872
DOI: 10.1016/j.ccr.2009.09.028

Experimental method

X-RAY DIFFRACTION (1.9 Å)