Monday, April 15, 2019

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
DOIhttps://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.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...