Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)

Dmytro Ostrovskyi; Tobias Rumpf; Julia Eib; Alexandre Lumbroso; Inna Slynko; Susan Klaeger; Stephanie Heinzlmeir; Michael Forster; Matthias Gehringer; Ellen Pfaffenrot; Silke Mona Bauer; Karin Schmidtkunz; Sandra Wenzler; Eric Metzger; Bernhard Kuster; Stefan Laufer; Roland Schüle; Wolfgang Sippl; Bernhard Breit; Manfred Jung

doi:10.4155/fmc-2016-0132

Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)

Dmytro Ostrovskyi, Tobias Rumpf, Julia Eib, Alexandre Lumbroso, Inna Slynko, Susan Klaeger, Stephanie Heinzlmeir, Michael Forster, Matthias Gehringer, Ellen Pfaffenrot, Silke Mona Bauer, Karin Schmidtkunz, Sandra Wenzler, Eric Metzger, Bernhard Kuster, Stefan Laufer, Roland Schüle, Wolfgang Sippl, Bernhard Breit, Manfred Jung

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

9 Scopus citations

Abstract

Aim: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro. Results: We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots. Conclusion: The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. </inline-graphic.

Original language	English
Pages (from-to)	1537-1551
Number of pages	15
Journal	Future Medicinal Chemistry
Volume	8
Issue number	13
DOIs	https://doi.org/10.4155/fmc-2016-0132
State	Published - Sep 2016

Keywords

SAR
epigenetics
histone phosphorylation
kinases
prostate cancer
proteomics
structure-activity relationship studies
tofacitinib

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.4155/fmc-2016-0132

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Ostrovskyi, D., Rumpf, T., Eib, J., Lumbroso, A., Slynko, I., Klaeger, S., Heinzlmeir, S., Forster, M., Gehringer, M., Pfaffenrot, E., Bauer, S. M., Schmidtkunz, K., Wenzler, S., Metzger, E., Kuster, B., Laufer, S., Schüle, R., Sippl, W., Breit, B., & Jung, M. (2016). Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1). Future Medicinal Chemistry, 8(13), 1537-1551. https://doi.org/10.4155/fmc-2016-0132

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title = "Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)",

abstract = "Aim: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro. Results: We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots. Conclusion: The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. ",

keywords = "SAR, epigenetics, histone phosphorylation, kinases, prostate cancer, proteomics, structure-activity relationship studies, tofacitinib",

author = "Dmytro Ostrovskyi and Tobias Rumpf and Julia Eib and Alexandre Lumbroso and Inna Slynko and Susan Klaeger and Stephanie Heinzlmeir and Michael Forster and Matthias Gehringer and Ellen Pfaffenrot and Bauer, {Silke Mona} and Karin Schmidtkunz and Sandra Wenzler and Eric Metzger and Bernhard Kuster and Stefan Laufer and Roland Sch{\"u}le and Wolfgang Sippl and Bernhard Breit and Manfred Jung",

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year = "2016",

month = sep,

doi = "10.4155/fmc-2016-0132",

language = "English",

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Ostrovskyi, D, Rumpf, T, Eib, J, Lumbroso, A, Slynko, I, Klaeger, S, Heinzlmeir, S, Forster, M, Gehringer, M, Pfaffenrot, E, Bauer, SM, Schmidtkunz, K, Wenzler, S, Metzger, E, Kuster, B, Laufer, S, Schüle, R, Sippl, W, Breit, B & Jung, M 2016, 'Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)', Future Medicinal Chemistry, vol. 8, no. 13, pp. 1537-1551. https://doi.org/10.4155/fmc-2016-0132

TY - JOUR

T1 - Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)

AU - Ostrovskyi, Dmytro

AU - Rumpf, Tobias

AU - Eib, Julia

AU - Lumbroso, Alexandre

AU - Slynko, Inna

AU - Klaeger, Susan

AU - Heinzlmeir, Stephanie

AU - Forster, Michael

AU - Gehringer, Matthias

AU - Pfaffenrot, Ellen

AU - Bauer, Silke Mona

AU - Schmidtkunz, Karin

AU - Wenzler, Sandra

AU - Metzger, Eric

AU - Kuster, Bernhard

AU - Laufer, Stefan

AU - Schüle, Roland

AU - Sippl, Wolfgang

AU - Breit, Bernhard

AU - Jung, Manfred

PY - 2016/9

Y1 - 2016/9

N2 - Aim: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro. Results: We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots. Conclusion: The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors.

AB - Aim: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro. Results: We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots. Conclusion: The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors.

KW - SAR

KW - epigenetics

KW - histone phosphorylation

KW - kinases

KW - prostate cancer

KW - proteomics

KW - structure-activity relationship studies

KW - tofacitinib

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DO - 10.4155/fmc-2016-0132

M3 - Article

C2 - 27572962

AN - SCOPUS:84986243088

SN - 1756-8919

VL - 8

SP - 1537

EP - 1551

JO - Future Medicinal Chemistry

JF - Future Medicinal Chemistry

IS - 13

ER -

Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)

Abstract

Keywords

UN SDGs

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