2,3,4,5-Tetrahydro-7-hydroxy-1H-benzofuro[2,3-c]azepin-1-one

Uses

Acts as a potent and selective inhibitor of protein kinase D (PKD1) .

Uses

CID755673 was used to study the role of PKD in dendrite retraction in mouse Purkinje cells.

Definition

ChEBI: 7-hydroxy-2,3,4,5-tetrahydrobenzofuro[2,3-c]azepin-1-one is a member of benzofurans.

General Description

A cell-permeable benzoxoloazepinolone compound that effectively inhibits syntide-2 (Cat. No. 05-23-4910) phosphorylation by all three PKD/PKCμ isoforms 1, 2, & 3 (IC₅₀ = 182, 280, and 227 nM, respectively), while exhibiting ≥30-fold less potency towards Cdk activating kinase, Plk1, CaMKIIα, as well as 44 other kinases, 33 of which are not significantly inhibited even at concentrations as high as 10 μM, including Akt1/2 and PKCα/β/δ/ζ. Shown to block PMA- (Cat. No. 524400) induced PKD1 phosphorylation on Ser⁷⁴² and Ser⁹¹⁶ in LNCaP cells, PMA-induced HCAS5 nuclear export in HeLa cells, as well as other PKD-mediated cellular responses. The mode of inhibition is demonstrated not to be ATP-competitive in nature. Also reported to inhibit MAPKAPK2, GSK-3β, CKIδ, MK5 (PRAK), CDK2, and Erk1 kinase activity at much elevated concentrations (% inhibition by 10 μM inhibitor = 95, 86, 82, 75, 71, and 50, respectively).

Biological Activity

cid755673, benzoxoloazepinolone, is the first identified cell-active small molecule pkd antagonist. it inhibits the activity of pkd1 with an ic50 of 182 nm and demonstrates highest selectivity to pkd1 when compared with akt, plk1, cak, camkiiα, pkd2 and pkd3. moreover, it was not competitive with atp for enzyme inhibition. [1]

Biochem/physiol Actions

CID755673 is a cell-permeable, potent and selective inhibitor of all three protein kinase D (PKD) isoforms PKD1 (PKCμ), PKD2, and PKD3 (PKCν). CID755673 is not competitive with ATP.

in vitro

in cell based assays, cid755673 dose-dependently suppressed pkd1 activation induced by phorbol ester endogenous in lncap cells. it was also reported to reverse biological actions of pkd1 including class iia histone deacetylase 5 nuclear exclusion, vesicular stomatitis, virus glycoprotein delivery from the golgi to the plasma membrane as well as the ilimaquinone-induced golgi fragmentation. moreover, cid755673 suppressed prostate cancer cell proliferation, cell migration, and invasion. [1]

in vivo

experimental models of acute pancreatitis were developed to study the effect of cid755673 on acute pancreatitis in vivo. results demonstrated that this compound suppressed pkd1/2 and therefore significantly offset necrosis and severity of pancreatitis. [2]

IC 50

selective protein kinase d (pkd) antagonist with the ic50 of 0.182, 0.280, 0.227, >10, 15.3, 20.3, 40.5 and >50 μm for pkd1, pkd2, pkd3, pkc, cak, plk1, camkiiα and akt respectively.

storage

Store at -20°C

References

[1]sharlow er, giridhar kv, lavalle cr, chen j, leimgruber s, barrett r, altamirano kb, wipf p, lazo js and wang qj. potent and selective disruption of protein kinase d functionality by a benzoxoloazepinolone. j biol chem. 2008 nov. 283(48): 3351246.
[2]yuan jz, liu yn, tan ty, guha s, gukovsky i, gukovskaya a and pandol sj. protein kinase d regulates cell death pathways in experimental pancreatitis. front physiol. 2012 mar. 3: doi: 10.3389/fphys.2012.00060.