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

doi:10.1016/j.chembiol.2019.02.015

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

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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, 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.

Original language	English
Pages (from-to)	804-817.e12
Journal	Cell Chemical Biology
Volume	26
Issue number	6
DOIs	https://doi.org/10.1016/j.chembiol.2019.02.015
State	Published - 20 Jun 2019
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Ltd

Funding

The authors would like to acknowledge Eric Wang and Milka Kostic for helpful comments on the manuscript. The authors would also like to acknowledge Matthew Robers and the scientists at Promega, for helpful discussion and protocol sharing related to the NanoBRET cellular target engagement assays. This work was supported by R35CA197588, P50-GM107618, U24-DK116204 R21CA188881, R01CA219850, the DFCI Strategic Research Initiative, and the Chleck Family Foundation, United States. F.M.F. designed and synthesized all compounds. Z.M.D. designed and conducted the experiments, and performed data analysis. S.B.F. and C.M.B. conducted MS experiments. M.J.B. and M.K. conducted the proteomics and phospho-proteomics experiments. J.L.J. and T.M.Y. conducted phospho-array experiments and peptide motif analysis. N.D.K. and T.S. performed all compound docking and modeling studies. F.M.F. and Z.M.D. wrote the manuscript, with guidance from N.S.G. J.A.M. L.C.C. and P.K.S. supervised the research. All authors gave feedback on the manuscript. L.C.C. is a founder and member of the Scientific Advisory Board (SAB) and holds equity in Agios Pharmaceuticals and Petra Pharmaceuticals. L.C.C. is also a member of the Board of Directors (BOD) of Agios and an observer on the BOD of Petra. Petra provides partial support for his laboratory. Both Agios and Petra are developing drugs for cancer therapies. J.M. is a member of the SAB of Devices. N.S.G. is a founder, SAB member, and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Her2llc, Deerfield, and Sanofi. N.S.G. F.M.F. and Z.M.D. are inventors on a patent application covering chemical matter in this publication owned by Dana-Farber Cancer Institute. P.K.S. is a founder, SAB member, and equity holder in Merrimack Pharmaceutical and Glencoe Software; he is on the BOD of Applied Biomath and the SAB of RareCyte. In the last 5 years the Sorger lab has received research funding from Novartis and Merck. P.K.S. declares that none of these relationships are directly or indirectly related to the content of this manuscript. N.S.G. is a founder, SAB member, and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis , Takeda , Astellas , Taiho , Jansen , Kinogen , Her2llc , Deerfield , and Sanofi . The authors would like to acknowledge Eric Wang and Milka Kostic for helpful comments on the manuscript. The authors would also like to acknowledge Matthew Robers and the scientists at Promega, for helpful discussion and protocol sharing related to the NanoBRET cellular target engagement assays. This work was supported by R35CA197588 , P50-GM107618 , U24-DK116204 R21CA188881 , R01CA219850 , the DFCI Strategic Research Initiative, and the Chleck Family Foundation, United States.

Funders	Funder number
Chleck Family Foundation
National Institute of General Medical Sciences	P50GM107618
Astellas Pharma US
Merck
Novartis
Sanofi
Takeda Pharmaceuticals U.S.A.
Dana-Farber Cancer Institute	R35CA197588, P50-GM107618, R01CA219850
Astellas Pharma Canada

Keywords

CDK14
TAIRE kinase
cell cycle
covalent inhibitor
druggable genome
mitosis

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10.1016/j.chembiol.2019.02.015

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Ferguson, F. M., Doctor, Z. M., Ficarro, S. B., Browne, C. M., Marto, J. A., Johnson, J. L., Yaron, T. M., Cantley, L. C., Kim, N. D., Sim, T., Berberich, M. J., Kalocsay, M., Sorger, P. K., & Gray, N. S. (2019). Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity. Cell Chemical Biology, 26(6), 804-817.e12. https://doi.org/10.1016/j.chembiol.2019.02.015

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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, 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.",

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AU - Kim, Nam Doo

AU - Sim, Taebo

AU - Berberich, Matthew J.

AU - Kalocsay, Marian

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AU - Gray, Nathanael S.

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AB - 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.

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Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity

Abstract

Bibliographical note

Funding

Keywords

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