7vds
The structure of cyclin-dependent kinase 5 (CDK5) in complex with p25 and Compound 24The structure of cyclin-dependent kinase 5 (CDK5) in complex with p25 and Compound 24
Structural highlights
FunctionCD5R1_HUMAN p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. Publication Abstract from PubMedAutosomal 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 GFB-12811, 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 in vivo PK profiles, enabling their use as tool compounds for interrogating the role of CDK5 in ADPKD and other diseases. Discovery and Optimization of Highly Selective Inhibitors of CDK5.,Daniels MH, Malojcic G, Clugston SL, Williams B, Coeffet-Le Gal M, Pan-Zhou XR, Venkatachalan S, Harmange JC, Ledeboer M J Med Chem. 2022 Feb 24;65(4):3575-3596. doi: 10.1021/acs.jmedchem.1c02069. Epub , 2022 Feb 10. PMID:35143203[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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