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Selective small-molecule inhibitors of protein kinases can serve as powerful tools to elucidate biological function. Efforts to develop potential drug candidates have yielded a wealth of kinase inhibitors. However, selecting the optimal kinase inhibitor for a particular application can be challenging. While the optimal inhibitor will be application specific, we have attempted to summarize some of the best reported inhibitors for various kinases. [ABSTRACT FROM AUTHOR]

Selective small-molecule inhibitors of protein kinases can serve as powerful tools to elucidate biological function. Efforts to develop potential drug candidates have yielded a wealth of kinase inhibitors. However, selecting the optimal kinase inhibitor for a particular application can be challenging. While the optimal inhibitor will be application specific, we have attempted to summarize some of the best reported inhibitors for various kinases. [ABSTRACT FROM AUTHOR]

Protein kinases are a large family of approximately 530 highly conserved enzymes that transfer a γ-phosphate group from ATP to a variety of amino acid residues, such as tyrosine, serine, and threonine, that serves as a ubiquitous mechanism for cellular signal transduction. The clinical success of a number of kinase-directed drugs and the frequent observation of disease causing mutations in protein kinases suggest that a large number of kinases may represent therapeutically relevant targets. To date, the majority of clinical and preclinical kinase inhibitors are ATP competitive, noncovalent inhibitors that achieve selectivity through recognition of unique features of particular protein kinases. Recently, there has been renewed interest in the development of irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket. Irreversible kinase inhibitors have a number of potential advantages including prolonged pharmacodynamics, suitability for rational design, high potency, and ability to validate pharmacological specificity through mutation of the reactive cysteine residue. Here, we review recent efforts to develop cysteine-targeted irreversible protein kinase inhibitors and discuss their modes of recognizing the ATP-binding pocket and their biological activity profiles. In addition, we provided an informatics assessment of the potential “kinase cysteinome” and discuss strategies for the efficient development of new covalent inhibitors. [ABSTRACT FROM AUTHOR]

Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development. • Our study highlights a multi-targeted strategy to identify druggable cysteines • We identified 23 covalent kinase targets across multiple spatial locations • Nine of these have previously not been covalently targeted by an inhibitor • Our findings highlight potential means to advance covalent drug discovery efforts The current work by Rao et al. describes using a promiscuous ligand as a tool to identify new targets for drug discovery. The findings from this study highlight previously unknown targets against which irreversible inhibitors can be developed. These targets are typically deregulated in diseases including cancer. [ABSTRACT FROM AUTHOR]

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. • A covalent, cell-permeable inhibitor of CDK14 was developed • Methods for assessing cellular engagement of TAIRE family kinases are described • Kinase motif analysis and phospho-proteomics identified putative CDK14 substrates Cyclin-dependent kinase 14 (CDK14) is an understudied kinase that lacks functional annotation. The authors develop and characterize a covalent CDK14 inhibitor, FMF-04-159-2, and use it to interrogate the role of CDK14 in the cell cycle and phospho-signaling. [ABSTRACT FROM AUTHOR]