3CS9

Human ABL kinase in complex with nilotinib

Summary for 3CS9

• Entry DOI: 10.2210/pdb3cs9/pdb
• Related: 2HYY
• Descriptor: Proto-oncogene tyrosine-protein kinase ABL1, Nilotinib (3 entities in total)
• Functional Keywords: nilotinib, amn107, kinase, abl, alternative splicing, atp-binding, cell adhesion, chromosomal rearrangement, cytoplasm, cytoskeleton, lipoprotein, magnesium, manganese, metal-binding, myristate, nucleotide-binding, nucleus, phosphoprotein, polymorphism, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase, abl kinase wt in complex with nvp-amn107
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 4
• Total formula weight: 130320.80

Authors

Cowan-Jacob, S.W.,Fendrich, G.,Manley, P.,Liebetanz, J.,Fabbro, D. (deposition date: 2008-04-09, release date: 2008-04-22, Last modification date: 2024-04-03)

Primary citation

Weisberg, E.,Manley, P.W.,Breitenstein, W.,Brueggen, J.,Cowan-Jacob, S.W.,Ray, A.,Huntly, B.,Fabbro, D.,Fendrich, G.,Hall-Meyers, E.,Kung, A.L.,Mestan, J.,Daley, G.Q.,Callahan, L.,Catley, L.,Cavazza, C.,Azam, M.,Neuberg, D.,Wright, R.D.,Gilliland, D.G.,Griffin, J.D.
Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl
Cancer Cell, 7:129-141, 2005

PubMed Abstract: The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.

PubMed: 15710326
DOI: 10.1016/j.ccr.2005.01.007

Experimental method

X-RAY DIFFRACTION (2.21 Å)