3KF4

Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template

3KF4 の概要

• エントリーDOI: 10.2210/pdb3kf4/pdb
• 関連するPDBエントリー: 3KFA
• 分子名称: Tyrosine-protein kinase ABL1, N-[4-(dimethylphosphoryl)phenyl]-9-[(E)-2-(5-methyl-1H-indazol-4-yl)ethenyl]-9H-purin-6-amine (3 entities in total)
• 機能のキーワード: abl, cml, drug resistance, inhibitor, atp-binding, kinase, nucleotide-binding, oncogene, tyrosine-protein kinase, 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: 67370.81

構造登録者

Zhou, T. (登録日: 2009-10-27, 公開日: 2009-12-22, 最終更新日: 2023-09-06)

主引用文献

Zhou, T.,Commodore, L.,Huang, W.S.,Wang, Y.,Sawyer, T.K.,Shakespeare, W.C.,Clackson, T.,Zhu, X.,Dalgarno, D.C.
Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.
Chem.Biol.Drug Des., 75:18-28, 2010

PubMed Abstract: Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure the purine template is bound deeply in the adenine pocket and the novel vinyl linker forms a non-classical hydrogen bond to the gatekeeper residue, Thr315. Specific template substitutions promote either a DFG-in or -out binding mode, with the kinase binding site adjusting to optimize molecular recognition. Bcr-Abl T315I mutant kinase is resistant to all currently marketed Abl inhibitors, and is the focus of intense drug discovery efforts. Notably, our DFG-out inhibitor, AP24163, exhibits modest activity against this mutant, illustrating that this kinase mutant can be inhibited by DFG-out class inhibitors. Furthermore our DFG-out inhibitor exhibits dual Src-Abl activity, absent from the prototypical DFG-out inhibitor, imatinib as well as its analog, nilotinib. The data presented here provides structural guidance for the further design of novel potent DFG-out class inhibitors against Src, Abl and Abl T315I mutant kinases.

PubMed: 19895503
DOI: 10.1111/j.1747-0285.2009.00905.x

実験手法

X-RAY DIFFRACTION (1.9 Å)