Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).

Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival, whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. SB203580, a p38 MAP kinase inhibitor, has been used as a tool to inhibit...

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Autores principales:	Giorgio Cozza, Sofia Zanin, Renate Determann, Maria Ruzzene, Conrad Kunick, Lorenzo A Pinna
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f305def2de64cbbae738c68cd18ff17
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spelling	oai:doaj.org-article:9f305def2de64cbbae738c68cd18ff172021-11-18T08:31:23ZSynthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).1932-620310.1371/journal.pone.0089176https://doaj.org/article/9f305def2de64cbbae738c68cd18ff172014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24586573/?tool=EBIhttps://doaj.org/toc/1932-6203Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival, whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. SB203580, a p38 MAP kinase inhibitor, has been used as a tool to inhibit HIPK2 in cells, but here we show that its efficacy as HIPK2 inhibitor is negligible (IC₅₀>40 µM). In contrast by altering the scaffold of the promiscuous CK2 inhibitor TBI a new class of HIPK2 inhibitors has been generated. One of these, TBID, displays toward HIPK2 unprecedented efficacy (IC₅₀ = 0.33 µM) and selectivity (Gini coefficient 0.592 out of a panel of 76 kinases). The two other members of the HIPK family, HIPK1 and HIPK3, are also inhibited by TBID albeit less efficiently than HIPK2. The mode of action of TBID is competitive with respect to ATP, consistent with modelling. We also provide evidence that TBID is cell permeable by showing that HIPK2 activity is reduced in cells treated with TBID, although with an IC₅₀ two orders of magnitude higher (about 50 µM) than in vitro.Giorgio CozzaSofia ZaninRenate DetermannMaria RuzzeneConrad KunickLorenzo A PinnaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e89176 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giorgio Cozza Sofia Zanin Renate Determann Maria Ruzzene Conrad Kunick Lorenzo A Pinna Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
description	Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival, whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. SB203580, a p38 MAP kinase inhibitor, has been used as a tool to inhibit HIPK2 in cells, but here we show that its efficacy as HIPK2 inhibitor is negligible (IC₅₀>40 µM). In contrast by altering the scaffold of the promiscuous CK2 inhibitor TBI a new class of HIPK2 inhibitors has been generated. One of these, TBID, displays toward HIPK2 unprecedented efficacy (IC₅₀ = 0.33 µM) and selectivity (Gini coefficient 0.592 out of a panel of 76 kinases). The two other members of the HIPK family, HIPK1 and HIPK3, are also inhibited by TBID albeit less efficiently than HIPK2. The mode of action of TBID is competitive with respect to ATP, consistent with modelling. We also provide evidence that TBID is cell permeable by showing that HIPK2 activity is reduced in cells treated with TBID, although with an IC₅₀ two orders of magnitude higher (about 50 µM) than in vitro.
format	article
author	Giorgio Cozza Sofia Zanin Renate Determann Maria Ruzzene Conrad Kunick Lorenzo A Pinna
author_facet	Giorgio Cozza Sofia Zanin Renate Determann Maria Ruzzene Conrad Kunick Lorenzo A Pinna
author_sort	Giorgio Cozza
title	Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
title_short	Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
title_full	Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
title_fullStr	Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
title_full_unstemmed	Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).
title_sort	synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (hipk2).
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/9f305def2de64cbbae738c68cd18ff17
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Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2).

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