3QRK

The crystal structure of human abl1 kinase domain in complex with DP-987

Summary for 3QRK

• Entry DOI: 10.2210/pdb3qrk/pdb
• Related: 3QRI 3QRJ
• Descriptor: Tyrosine-protein kinase ABL1, (3S)-6-(3-tert-butyl-5-{[(2,3-dichlorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3 entities in total)
• Functional Keywords: abl1, kinase, kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 1
• Total formula weight: 32613.13

Authors

Chan, W.W.,Wise, S.C.,Kaufman, M.D.,Ahn, Y.M.,Ensinger, C.L.,Haack, T.,Hood, M.M.,Jones, J.,Lord, J.W.,Lu, W.P.,Miller, D.,Patt, W.C.,Smith, B.D.,Petillo, P.A.,Rutkoski, T.J.,Telikepalli, H.,Vogeti, L.,Yao, T.,Chun, L.,Clark, R.,Evangelista, P.,Gavrilescu, L.C.,Lazarides, K.,Zaleskas, V.M.,Stewart, L.J.,Van Etten, R.A.,Flynn, D.L. (deposition date: 2011-02-18, release date: 2011-06-01, Last modification date: 2024-04-03)

Primary citation

Chan, W.W.,Wise, S.C.,Kaufman, M.D.,Ahn, Y.M.,Ensinger, C.L.,Haack, T.,Hood, M.M.,Jones, J.,Lord, J.W.,Lu, W.P.,Miller, D.,Patt, W.C.,Smith, B.D.,Petillo, P.A.,Rutkoski, T.J.,Telikepalli, H.,Vogeti, L.,Yao, T.,Chun, L.,Clark, R.,Evangelista, P.,Gavrilescu, L.C.,Lazarides, K.,Zaleskas, V.M.,Stewart, L.J.,Van Etten, R.A.,Flynn, D.L.
Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036.
Cancer Cell, 19:556-568, 2011

PubMed Abstract: Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.

PubMed: 21481795
DOI: 10.1016/j.ccr.2011.03.003

Experimental method

X-RAY DIFFRACTION (2.3 Å)