Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity

Fleur M Ferguson, Zainab M Doctor, Scott B Ficarro, Christopher M Browne, Jarrod A Marto, Jared L Johnson, Tomer M Yaron, Lewis C Cantley, Nam Doo Kim, Taebo Sim, Matthew J Berberich, Marian Kalocsay, Peter K Sorger, Nathanael S Gray

Cell Chemical Biology, 2019
DOI: https://doi.org/10.1016/j.chembiol.2019.02.015


Cyclin-dependent kinase 14 (CDK14) and other TAIRE family kinases (CDKs 15–18) are proteins that lack functional annotation but are frequent off-targets of clinical kinase inhibitors. In this study we develop and characterize FMF-04-159-2, a tool compound that specifically targets CDK14 covalently and possesses a TAIRE kinase-biased selectivity profile. This tool compound and its reversible analog were used to characterize the cellular consequences of covalent CDK14 inhibition, including an unbiased investigation using phospho-proteomics. To reduce confounding off-target activity, washout conditions were used to deconvolute CDK14-specific effects. This investigation suggested that CDK14 plays a supporting role in cell-cycle regulation, particularly mitotic progression, and identified putative CDK14 substrates. Together, these results represent an important step forward in understanding the cellular consequences of inhibiting CDK14 kinase activity.