Tyrosine-protein kinase Fes/Fps (also known as proto-oncogene c-Fes/Fps) and together with the homologous kinase Fer, defines a structurally unique kinase family. c-Fes is present in a variety of cell lineages, including myeloid hematopoietic, vascular endothelial, neuronal and epithelial cells. Active c-Fes has been observed in acute myeloid leukemia (AML), and reduction of c-fes expression by RNAi demonstrated a requirement for c-Fes in AML cell survival.
Selective small molecule inhibitors are urgently needed to clarify the roles of c-Fes as dominant oncogene vs. tumor suppressor depending upon the cellular context. Despite the intriguing biology associated with c-Fes, very limited inhibitors with a useful level of selectivity and cellular activity have been reported to date.
TAE684, a compound previously identified as a potent and selective inhibitor of the anaplastic lymphoma kinase (ALK), is also a potent inhibitor of c-Fes both in vitro and in vivo. WZ-4-49-8 as well as HG-7-92-01 demonstrated strong inhibition of c-Fes in vitro. WZ-4-49-8 potently inhibited c-Fes-L145P-mediated soft-agar colony growth and showed remarkable selectivity for c-Fes-L145P over several active SFKs tested.
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WZ-4-49-8 is a potent, selective c-Fes protein-tyrosine kinase inhibitor with IC50 of 67 nM; displays an exceptional selectivity profile with a selectivity score of only 0.027 in a panel of 442 kinases; inhibits c-Fes-L145P autophosphorylation and microtubule association in at least a subset of cells, and potently inhibits c-Fes-L145P-mediated soft-agar colony growth; dramatically inhibits osteoclast differentiation in RAW 264.7 macrophage cell line.
HG-7-27-01 is a potent, selective c-Fes protein-tyrosine kinase inhibitor with IC50 of 224 nM, displays intermediate selectivity profiles (selectivity score=0.16) against 442 kinases.
HG-7-92-01 is a potent, selective c-Fes protein-tyrosine kinase inhibitor with IC50 of 292 nM, displays intermediate selectivity profiles (selectivity score=0.18) against 353 kinases.
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