6VHG

Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrazolo[1,5-a]pyrimidine inhibitor

6VHG の概要

• エントリーDOI: 10.2210/pdb6vhg/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase receptor Ret, 3-(3,4-dimethoxyphenyl)-N~5~-(1-methylpiperidin-4-yl)-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: inhibitor, complex, tyrosine kinase, catalytic domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36501.53

構造登録者

Lee, C.C.,Spraggon, G. (登録日: 2020-01-09, 公開日: 2020-02-26, 最終更新日: 2024-10-23)

主引用文献

Mathison, C.J.N.,Chianelli, D.,Rucker, P.V.,Nelson, J.,Roland, J.,Huang, Z.,Yang, Y.,Jiang, J.,Xie, Y.F.,Epple, R.,Bursulaya, B.,Lee, C.,Gao, M.Y.,Shaffer, J.,Briones, S.,Sarkisova, Y.,Galkin, A.,Li, L.,Li, N.,Li, C.,Hua, S.,Kasibhatla, S.,Kinyamu-Akunda, J.,Kikkawa, R.,Molteni, V.,Tellew, J.E.
Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.
Acs Med.Chem.Lett., 11:558-565, 2020

PubMed Abstract: RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse studies, compound demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of , however, were poorly tolerated in mice, similar to other pyrazolo[1,5-]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

PubMed: 32292564
DOI: 10.1021/acsmedchemlett.0c00015

実験手法

X-RAY DIFFRACTION (2.303 Å)