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Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C.

Abstract：

:Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC delta C1b domain, we have discovered conveniently synthesizable derivatives of dialkyl 5-(hydroxymethyl)isophthalate that can act as potential C1 domain ligands. Structure-activity studies confirmed that the important functional groups predicted by modeling were indispensable for binding to the C1 domain and that the modifications of these groups diminished binding. The most promising compounds were able to displace radiolabeled phorbol ester ([(3)H]PDBu) from PKC alpha and delta at K(i) values in the range of 200-900 nM. Furthermore, the active isophthalate derivatives could modify PKC activation in living cells either by inducing PKC-dependent ERK phosphorylation or by inhibiting phorbol-induced ERK phosphorylation. In conclusion, we report here, for the first time, that derivatives of isophthalic acid represent an attractive novel group of C1 domain ligands that can be used as research tools or further modified for potential drug development.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Boije af Gennäs G,Talman V,Aitio O,Ekokoski E,Finel M,Tuominen RK,Yli-Kauhaluoma J

doi

10.1021/jm900229p

subject

Has Abstract

pub_date

2009-07-09 00:00:00

pages

3969-81

issue

13

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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