1-NM-PP1

1-NM-PP1 is a cell permeable inhibitor of kinases that have been mutated, by a single base substitution, to become ‘analog sensitive’ (as), as compared to the wild-type kinase. 1-NM-PP1 was first developed to optimally inhibit v-Src-as1, with an I338G substitution, preferentially over v-Src (IC₅₀ = 4.2 nM versus 28 μM, respectively).¹ The homologous mutation in other kinases generated similar analog sensitivity (e.g., IC₅₀ = 3.2 nM for c-Fyn-as1 versus 1.0 μM for c-Fyn; 5.0 nM for Cdk2-as1 versus 29 μM for Cdk2; 8.0 nM for CAMKII-as1 versus 24 μM for CAMKII).² This approach has been used to elucidate functions of several kinases in both mammalian and yeast systems.^2,3,4,5,6

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1. Bishop, A.C., Kung, C.y., Shah, K., et al. Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach. J. 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 kinase. Nature 407(6802), 395-401 (2000).

3. Weiss, E.L., Bishop, A.C., Shokat, K.M., et al. Chemical genetic analysis of the budding-yeast p21-activated kinase Cla4p. Nat. Cell Biol. 2(10), 677-685 (2000).

4. Ira, G., Pellicioli, A., Balijja, A., et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431(7011), 1011-1017 (2004).

5. Larochelle, S., Merrick, K.A., Terret, M.E., et al. Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol. Cell 25(6), 839-850 (2007).

6. Van den Broeke, C., Radu, M., Deruelle, M., et al. Alphaherpesvirus US3-mediated reorganization of the actin cytoskeleton is mediated by group A p21-activated kinases. Proc. Natl. Acad. Sci. USA 106(21), 8707-8712 (2009).