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Cyclin-dependent kinase-like 2 (CDKL2) is a serine/threonine kinase with reported links to development and cancer. A new study involving collaboration between the Bullock group at CMD Oxford and Alison Axtman at SGC-UNC reports the first chemical probe for CDKL2 providing an important reagent to interrogate CDKL2-dependent biology.

CDKL2

 

CDKL2 is an understudied kinase belonging to the CMGC kinase group and CDKL family.  It shares features with both the MAPK and CDK families, although it does not appear to require a cyclin subunit for activity. We report the small molecule “SGC-CDKL2-1” as the first chemical probe for CDKL2, as well as a matched negative control compound “SGC-CDKL2-1N”. The probe has an in vitro IC50 value of 43 nM and cellular IC50 of 460 nM in a nanoBRET assay. A crystal structure of CDKL2 bound to the acylaminoindazole scaffold of SGC-CDKL2-1 revealed a large hydrophobic pocket that encloses the probe’s sulfonamide moiety which likely contributes to its high selectivity over other kinases. The work is published in the journal ACS Med. Chem. Lett.