Discovery of covalent CDK14 inhibitors with pan-TAIRE family specificity

ABSTRACT: 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, the first 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 using proteomics and phospho-proteomics experiments to characterize compound effects. Together these results represent an important step forward in understanding the cellular consequences of inhibiting CDK14 kinase activity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

DISEASE(S): Colon Cancer

SUBMITTER: Matthew Berberich  

LAB HEAD: Nathanael S. Gray

PROVIDER: PXD012692 | Pride | 2019-03-29

REPOSITORIES: Pride