3IK3

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

3IK3 の概要

• エントリーDOI: 10.2210/pdb3ik3/pdb
• 分子名称: 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)
• 機能のキーワード: 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
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Cytoplasm, cytoskeleton: P00520
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67573.16

構造登録者

Zhou, T. (登録日: 2009-08-05, 公開日: 2009-11-03, 最終更新日: 2023-09-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.9 Å)