3F3W

Drug resistant cSrc kinase domain in complex with inhibitor RL45 (Type II)

3F3W の概要

• エントリーDOI: 10.2210/pdb3f3w/pdb
• 関連するPDBエントリー: 2QI8 2QLQ 2QQ7 3F3T 3F3U 3F3V
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 1-{4-[(6-aminoquinazolin-4-yl)amino]phenyl}-3-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea (3 entities in total)
• 機能のキーワード: allosteric, type ii, dfg-out, drug resistance mutation, alternative splicing, atp-binding, kinase, lipoprotein, myristate, nucleotide-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• 由来する生物種: Gallus gallus (Chicken)
• 細胞内の位置: Cell membrane (By similarity): P00523
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66558.81

構造登録者

Grutter, C.,Kluter, S.,Getlik, M.,Rauh, D. (登録日: 2008-10-31, 公開日: 2009-06-02, 最終更新日: 2023-11-01)

主引用文献

Getlik, M.,Grutter, C.,Simard, J.R.,Kluter, S.,Rabiller, M.,Rode, H.B.,Robubi, A.,Rauh, D.
Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
J.Med.Chem., 52:3915-3926, 2009

PubMed Abstract: The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.

PubMed: 19462975
DOI: 10.1021/jm9002928

実験手法

X-RAY DIFFRACTION (2.6 Å)