3QRI

The crystal structure of human abl1 kinase domain in complex with DCC-2036

3QRI の概要

• エントリーDOI: 10.2210/pdb3qri/pdb
• 関連するPDBエントリー: 3QRJ 3QRK
• 分子名称: Tyrosine-protein kinase ABL1, SODIUM ION, 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, ... (4 entities in total)
• 機能のキーワード: abl1, kinase, kinase domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65374.62

構造登録者

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. (登録日: 2011-02-18, 公開日: 2011-06-01, 最終更新日: 2024-04-03)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)