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Unique inhibitory action of the synthetic compound 2-[N-(2-aminoethyl)-N-(5-isoquinolinesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (CKA-1306) against calcium/calmodulin-dependent protein kinase I.

Abstract：

:A newly synthesized compound, 2-[N-(2-aminoethyl)-N-(5-isoquinolinesulfonyl)]amino-N-(4-chlorocinnamyl )-N-methylbenzylamine (CKA-1306), was found to inhibit cyclic AMP-dependent protein kinase (PKA) and Ca2+/calmodulin-dependent protein kinase I (CaMK I) with IC50 values of 1.6+/-0.14 and 2.5+/-0.16 microM, respectively. In contrast, the established PKA inhibitors H-8 and H-89 inhibited CaMK I with relatively high IC50 values of >100 and 24.4+/-3.2 microM, respectively. An additional inhibitor, KN-62, against Ca2+/calmodulin-dependent protein kinase II (CaMK II) did not inhibit either PKA or CaMK I at the concentrations tested. In our library of many isoquinolinesulfonamide derivatives, only CKA-1306 inhibited CaMK I to a satisfactory degree, suggesting a unique mode of action. Indeed, the inhibition of CaMK I by CKA-1306 was competitive in every respect to Mg2+/ATP, peptide substrate (syntide-2), and Ca2+/calmodulin. This phenomenon may be understood from the context of the recently determined structure of the enzyme in its autoinhibited state. Such kinetic analysis was also extended to cases using a phosphorylated and activated enzyme at Thr177 or a constitutively active, COOH-terminal truncated mutant at Gln293. CKA-1306 still competed with Mg2+/ATP for the two enzymes, but it no longer achieved any competitive advantage over syntide-2. These results may reflect some differences in the active conformation of CaMK I. However, the compound should be constant in its recognition of an Mg2+/ATP-binding site of the enzyme. Though CKA-1306 is not specific to CaMK I, the compound will be useful in studying the enzyme further under limited conditions.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Sakaguchi H,Yokokura H,Terada O,Naito Y,Nimura Y,Hidaka H

doi

10.1016/s0006-2952(98)00157-9

subject

Has Abstract

pub_date

1998-08-01 00:00:00

pages

329-34

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(98)00157-9

journal_volume

pub_type

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Unique inhibitory action of the synthetic compound 2-[N-(2-aminoethyl)-N-(5-isoquinolinesulfonyl)] amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (CKA-1306) against calcium/calmodulin-dependent protein kinase I.