4PMM

The structure of TrkA kinase bound to the inhibitor N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-{4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl}acetamide

4PMM の概要

• エントリーDOI: 10.2210/pdb4pmm/pdb
• 関連するPDBエントリー: 4PMP 4PMS 4PMT
• 分子名称: High affinity nerve growth factor receptor, N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-{4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl}acetamide, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : P04629
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34031.59

構造登録者

Su, H.P. (登録日: 2014-05-22, 公開日: 2014-06-18, 最終更新日: 2023-12-27)

主引用文献

Stachel, S.J.,Sanders, J.M.,Henze, D.A.,Rudd, M.T.,Su, H.P.,Li, Y.,Nanda, K.K.,Egbertson, M.S.,Manley, P.J.,Jones, K.L.,Brnardic, E.J.,Green, A.,Grobler, J.A.,Hanney, B.,Leitl, M.,Lai, M.T.,Munshi, V.,Murphy, D.,Rickert, K.,Riley, D.,Krasowska-Zoladek, A.,Daley, C.,Zuck, P.,Kane, S.A.,Bilodeau, M.T.
Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
J.Med.Chem., 57:5800-5816, 2014

PubMed Abstract: We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

PubMed: 24914455
DOI: 10.1021/jm5006429

実験手法

X-RAY DIFFRACTION (2 Å)