1-NA-PP1 is a reversible, cell-permeable inhibitor of Src-family tyrosine kinases that have been mutated, by a single base substitution, to become ‘analog sensitive’ (as), as compared to the wild-type kinase. 1-NA-PP1 was first developed to optimally inhibit v-Src-as1, with an I338G substitution, preferentially over v-Src (IC50 = 1.5 nM versus 1.0 μM, respectively).1 The homologous mutation in other kinases generated similar analog sensitivity (e.g., IC50 = 1.5 nM for c-Fyn-as1 versus 0.6 μM for c-Fyn; 7.0 nM for c-Abl-as2 versus 0.6 μM for c-Abl; 15 nM for Cdk2-as1 versus 18 μM for Cdk2).2 This approach has been used to elucidate functions of several kinases in both mammalian and yeast systems.2,3,4
1.Bishop, A.C., Kung, C.y., Shah, K., et al.Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approachJ. Am. Chem. Soc.121(4)627-631(1999)
2.Bishop, A.C., Ubersax, J.A., Petsch, D.T., et al.A chemical switch for inhibitor-sensitive alleles of any protein kinaseNature407(6802)395-401(2000)
3.Endo, S., Satoh, Y., Shah, K., et al.A single amino-acid change in ERK1/2 makes the enzyme susceptible to PP1 derivativesBiochem. Biophys. Res. Commun.341261-265(2006)
4.Kenski, D.M., Zhang, C., von Zastrow, M., et al.Chemical genetic engineering of G protein-coupled receptor kinase 2J. Biol. Chem.280(41)35051-35061(2005)
