N-(2-[p-Bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride

Description

H-89 (127243-85-0) is a commonly used inhibitor of protein kinase A (PKA IC50= 140 nM). Inhibits a variety of other kinases including S6K1 (IC50= 80 nM), MSK1 (120 nM), ROCK II (270 nM), PKBα (2.6 μM), PKD, PRK2, RSK1 and 2, SGK, AMPK, CHK1 and MAPKAP-K1b (2.8 μM).1,2

Chemical Properties

White Solid

Uses

Selective inhibitor of Protein Kinase A (cyclic AMP-dependeant Protein Kinase) with an inhibitory constant of 0.0048 uM.

Definition

ChEBI: A member of the class of isoquinolines that is the sulfonamide obtained by formal condensation of the sulfo group of isoquinoline-5-sulfonic acid with the primary amino group of N1-[3-(4-bromophenyl)prop-2-en-1-yl]et ane-1,2-diamine.

General Description

A cell-permeable, selective, reversible, ATP-competitive and potent inhibitor of protein kinase A (K_i = 48 nM). Inhibits other kinases at several fold higher concentrations: myosin light chain kinase (K_i = 28.3 μM), Ca²⁺/calmodulin-dependent protein kinase II (K_i = 29.7 μM), protein kinase C (K_i = 31.7 μM), casein kinase I (K_i = 38.3 μM), and Rho Kinase II (IC₅₀ = 270 nM). May be used to discriminate between the effects of PKA and cAMP-regulated guanine-nucleotide-exchange factors (GEFs), such as GEFI or Epac (exchange protein directly activated by cAMP) and GEFII. Reported to induce neurite formation in NG 108-15 cells (~1 mM) by blocking the action of Rho kinase II.

Biological Activity

Protein kinase A inhibitor that also inhibits several other kinases (IC 50 values are 80, 120, 135, 270, 2600 and 2800 nM for S6K1, MSK1, PKA, ROCKII, PKB α and MAPKAP-K1b).

Biochem/physiol Actions

Target Ki: 48 nM for protein kinase A

Background

H-89 is a potent selective inhibitor of cAMP dependent protein kinase. The in vitro IC50 of H-89 for PKA is approximately 50 nM and in vivo the inhibitiory effect on PKA substrate phosphorylation and related cellular functions range from 10 μM to 30 μM. In addition to PKA, H-89 also exhibits a moderate inhibitory effect on PKG and PKCμ, with IC50 in the 500 nM range. The inhibitory effect of H-89 is due to its competitive binding to the ATP pocket on the kinase catalytic subunit.

References

[1] A. LOCHNER  J. A M. The Many Faces of H89: A Review[J]. Cardiovascular Therapeutics, 2007, 24 3-4: 261-274. DOI:10.1111/j.1527-3466.2006.00261.x
[2] JENNY BAIN. The selectivity of protein kinase inhibitors: a further update.[J]. Biochemical Journal, 2007: 297-315. DOI:10.1042/bj20070797