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


ABSTRACT: 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 (IC??>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 (IC???=?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 IC?? two orders of magnitude higher (about 50 µM) than in vitro.

SUBMITTER: Cozza G 

PROVIDER: S-EPMC3933419 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Cozza Giorgio G   Zanin Sofia S   Determann Renate R   Ruzzene Maria M   Kunick Conrad C   Pinna Lorenzo A LA  

PloS one 20140224 2


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 inhibit  ...[more]

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