7VDP

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

Summary for 7VDP

• Entry DOI: 10.2210/pdb7vdp/pdb
• Descriptor: 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)
• Functional Keywords: cdk5, p25, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 115318.55

Authors

Malojcic, G.,Clugston, S.L.,Daniels, M.,Harmange, J.C.,Ledeborer, M. (deposition date: 2021-09-07, release date: 2022-03-09, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.09 Å)