Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity

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

doi:10.1016/j.chembiol.2019.02.015

Cited by 27 publications

(19 citation statements)

References 51 publications

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“…Although our analysis failed to uncover selective modulators of these CDKs, the energy transfer-based probes developed in this work can be used to identify and optimize potential tool molecules for these understudied but important family members. Encouragingly, during the preparation of this manuscript a number of inhibitors were reported for understudied CDKs including the TAIRE subfamily 60 as well as CDK11 61 . As our compound panel represents only a fraction of known CDKi's, the results presented here suggest that comprehensive assessments of CDK target engagement are warranted as a standard practice for all novel tool compounds and promising clinical leads that are beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

Quantifying CDK inhibitor selectivity in live cells

et al. 2020

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Concerted multidisciplinary efforts have led to the development of Cyclin-Dependent Kinase inhibitors (CDKi's) as small molecule drugs and chemical probes of intracellular CDK function. However, conflicting data has been reported on the inhibitory potency of CDKi's and a systematic characterization of affinity and selectivity against intracellular CDKs is lacking. We have developed a panel of cell-permeable energy transfer probes to quantify target occupancy for all 21 human CDKs in live cells, and present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of 46 clinically-advanced CDKi's and tool molecules. We observed unexpected intracellular activity profiles for a number of CDKi's, offering avenues for repurposing of highly potent molecules as probes for previously unreported targets. Overall, we provide a broadly applicable method for evaluating the selectivity of CDK inhibitors in living cells, and present a refined set of tool molecules to study CDK function.

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Section: Discussionmentioning

confidence: 99%

Quantifying CDK inhibitor selectivity in live cells

et al. 2020

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“…As kinases are typically druggable targets which can be inhibited in non-invasive ways ( 39 ), we next asked whether CDK14 pharmacological inhibition would be a tractable route for decreasing α-Syn levels. We used a recently developed CDK14 covalent inhibitor (FMF-04-159-2) ( 26 ) to test whether acute depletion of CDK14 decreased α-Syn levels. We found that in HEK293T cells, CDK14 inhibition induced a strong reduction in endogenous α-Syn protein levels ( Fig 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…Its expression is upregulated in certain cancers, such as esophageal and colorectal cancer, for which it has generated attention as a therapeutic target ( 24 , 25 ). In fact, this has led to the recent development of FMF-04-159-2, a potent, covalent inhibitor of CDK14 ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease

Parmasad

Ricke

Stykel

et al. 2022

Preprint

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Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of alpha-Synuclein (a-Syn) protein. Currently, no treatment can slow nor halt neurodegeneration. Multiplications and mutations of the a-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress a-Syn replicate several features of PD. Decreasing total a-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with a 'synucleinopathy'. We previously performed a genetic screen for modifiers of a-Syn levels, and found CDK14, a kinase of largely unknown function as a regulator of a-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we decreased Cdk14 in two mouse models of synucleinopathy. We found that reduction of Cdk14 mitigated neuropathological and neurobehavioral sequelae associated with a-Syn overexpression. We further validated these findings in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable ex vivo. We found that in both mouse and human neurons, CDK14 inhibition decreases total and pathologically aggregated a-Syn. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.

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“…When examining CCNY:Cdk14, a membrane complex linked to Wnt signaling whose peak expression is thought during M phase [12,[67][68][69], Cdk14 overexpression without its CCNY regulator was found to correspond indirectly with proliferation gene expression and directly with co-expression of hedgehog signaling and epithelial to mesenchyme transition (EMT) genes, in COAD and most LUAD. The few COAD with Cdk14 mutations appeared to reverse the heatmap expression patterns for proliferation, hedgehog signaling, and EMT components.…”

Section: Discussionmentioning

confidence: 99%

Co-expression Patterns Explain how a Basic Transcriptional Role for MYC Modulates Wnt and MAPK Pathways in Colon and Lung Adenocarcinomas

Kucherlapati

2021

Preprint

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Genome duplication begins at many epigenetically determined sites by pre-replication, pre-initiation, and replisome complexes; co-expression of their components must be optimally timed for S phase to occur. Oscillations of cyclin dependent kinases (Cdks) and regulator cyclins control cell cycling, many are pharmacological targets in cancer. This study examines gene expression relationships between drivers, cell cycle components, and a subset of proliferation genes in colon (COAD) and lung (LUAD) adenocarcinomas. Several known drivers of COAD and LUAD including APC, CTNNB1, KRAS, MYC, Braf, TP53, Rb1, and EGFR are also observed with focus on Wnt and MAPK signaling activation. Wnt signaling activation has relevance for immune checkpoint inhibitor therapy, as it provides cancer cells with escape mechanisms.MYC and KRAS co-expressed directly with far fewer proliferation genes in LUAD than COAD, suggesting their expression is ectopic to S phase in lung tumors. APC indirectly co-expressed with the same factors in both COAD and LUAD, but was found co-expressed indirectly with MYC and mutated only in COAD. Other Wnt signaling components also co-expressed in low MYC context in COAD, had significantly higher mutation frequencies. These data suggest Wnt signaling activation to be the indirect result of decreased MYC availability in COAD, and ectopic overexpression of MYC in LUAD. Cyclins CCNH, CCNC, and CCNK, co-expressed with far fewer proliferation genes in LUAD. Conversely, Braf had direct co-expression with many proliferation factors in non EGFR activated LUAD. Proliferation in EGFR activated LUAD was completely deregulated with E2F(s) 4/5/6 expression, potentially explaining their low proliferative ability.

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Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity

Abstract: Highlights d A covalent, cell-permeable inhibitor of CDK14 was developed d Methods for assessing cellular engagement of TAIRE family kinases are described d Kinase motif analysis and phospho-proteomics identified putative CDK14 substrates

Cited by 27 publications

References 51 publications

Quantifying CDK inhibitor selectivity in live cells

Quantifying CDK inhibitor selectivity in live cells

Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease

Co-expression Patterns Explain how a Basic Transcriptional Role for MYC Modulates Wnt and MAPK Pathways in Colon and Lung Adenocarcinomas

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