7VDP

The structure of cyclin-dependent kinase 5 (CDK5) in complex with p25 and Compound 1

7VDP の概要

• エントリーDOI: 10.2210/pdb7vdp/pdb
• 分子名称: Cyclin-dependent-like kinase 5, Cyclin-dependent kinase 5 activator 1, p25, [1-[3-fluoranyl-4-[(2-piperidin-4-yloxy-1,6-naphthyridin-7-yl)amino]phenyl]pyrazol-3-yl]methanol, ... (8 entities in total)
• 機能のキーワード: cdk5, p25, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 115318.55

構造登録者

Malojcic, G.,Clugston, S.L.,Daniels, M.,Harmange, J.C.,Ledeborer, M. (登録日: 2021-09-07, 公開日: 2022-03-09, 最終更新日: 2023-11-29)

主引用文献

Daniels, M.H.,Malojcic, G.,Clugston, S.L.,Williams, B.,Coeffet-Le Gal, M.,Pan-Zhou, X.R.,Venkatachalan, S.,Harmange, J.C.,Ledeboer, M.
Discovery and Optimization of Highly Selective Inhibitors of CDK5.
J.Med.Chem., 65:3575-3596, 2022

PubMed Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic human disease, but to date, only one therapy (tolvaptan) is approved to treat kidney cysts in ADPKD patients. Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase family, has been implicated as a target for treating ADPKD. However, no compounds have been disclosed to date that selectively inhibit CDK5 while sparing the broader CDK family members. Herein, we report the discovery of CDK5 inhibitors, including , that are highly selective over the other tested kinases. In cellular assays, our compounds demonstrate CDK5 target engagement while avoiding anti-proliferative effects associated with inhibiting other CDKs. In addition, we show that the compounds in this series exhibit promising PK profiles, enabling their use as tool compounds for interrogating the role of CDK5 in ADPKD and other diseases.

PubMed: 35143203
DOI: 10.1021/acs.jmedchem.1c02069

実験手法

X-RAY DIFFRACTION (2.09 Å)