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kinases PKC inhibitors



Dear Kinase folk,

There have been a number of questions about PKC inhibitors in the last few
months which prompted me to post this.  During a recent trawl of catalogues
and literature I came up with the following list of isozyme selective PKC
inhibitors.  Inhibitors of total PKC activity also exist (e.g.
chelerythrine chloride), but I was more interested in isozyme selectivity.
Literature searches indicate that peptide inhibitors of PKC isozymes
(generally based on pseudosubstrate sequences) are very good, but I don't
think they are suitable for my whole mouse embryo culture experiments,
where crossing membranes could be limiting.  I must stress that the
following list is based on literature rather than personal experience, so I
would be grateful for any additions, comments or corrections.  Furthermore
it is important to realise that in a lot of the studies that provide the
data below an incomplete set of PKC isozymes were tested.  The most
important point is that there is no substitute for PKC assays to check that
your chosen inhibitor is really inactivating the PKC isoforms you intended. 

Numbers in brackets represent IC50 unless otherwise indicated.

Inhibitor			Company		Inhibits

Go6976				Calbiochem		alpha (2.3 nM) beta (6.2nM) (not delta 				Biomol
epsilon, zeta)
			

Go6983				Calbiochem		alpha (7nM) beta (7nM) gamma (6nM) delta
(10nM) zeta (60nM)

Rottlerin			Calbiochem		delta (3-6nM) alpha beta gamma (all 30-42 (=
Mallatoxin)						nM) epsilon eta zeta (all 80-100mM)


HBDDE				Biomol			alpha (43mM) gamma (50mM) (not delta (staurosporine
beta1 	beta2)
analogue)
							

GF109203X			Biomol			alpha (8.4nM) beta (18nM) gamma (?) delta (=Go6850)
		(210nM) epsilon (132nM) zeta (5800nM)
(=Bis I)						(GF109203X is a bisindolylmaleimide, so 							can use Bis5
as a negative control)
							Note: GF109203X also inhibits MAPKAP 							kinase-1b (50nM) and p70
S6 kinase(100nM)

UCN-01				Yokohoma City Uni?	alpha (Ki 0.44nM) cPKCs (Ki 1 nM) nPKCs (=
7-hydroxystaurosporine)				(Ki 20nM) z (Ki 3.8mM) 


R0-32-0432			Calbiochem		alpha (9nM) betaI (28nM) betaII (31nM)
gamma (37nM) epsilon (108nM)
R0-31-7208			?			alpha (160nM) betaI (310nM) betaII 							(280nM) gamma
(377nM) epsilon (330nM)
R0-31-7549			?			alpha (53nM) betaI (195nM) betaII (163nM) 							gamma
(213nM) epsilon (175nM)
R0-31-8220			?			alpha (5nM) betaI (24nM) betaII (14nM)   							gamma
(27nM) epsilon (24nM)
R0-31-8425			?			alpha (8nM) betaI (8nM) betaII (14nM) 							gamma (13nM)
epsilon (39nM)

LY333531			Eli Lilly		betaI (4.7nM) betaII (5.9nM) ~70-fold 							more
potent than for alpha (gamma delta 							epsilon eta not affected)

CGP 41-251			?			?
							(CGP 42-700 is an inactive analogue of 							CGP 41-251 and can be
used as a negative 							control)
 
Regards,

Andrew.

P.S. Apologise if the formatting did not survive your e-mail decoding.
Andrew, M. Hynes PhD,
Neural Development Unit,
Institute of Child Health,
30 Guilford Street,
London WC1N 1EH,
United Kingdom
Tel: 44-171-905-2230
E-mail: A.Hynes@ich.ucl.ac.uk