eCF506

This probe is selective for SRC over ABL, but only a small number of off-target kinases (15) were screened. It appears to be equipotent against YES and is thus at least a dual inhibitor (SRC/YES). It also appears to be suitable for use in cells and in vivo.

This is an ATP-competitive SRC inhibitor, selective for Src-family kinases over ABL1. In MCF7 cells, it inhibits auto-phosphorylation of SRC pY416 and its downstream substrate FAK pY861 at low nanomolar concentrations, with complete inhibition observed at 100 nM. Treatment halts migration of MDA-MB-231 cells at 10 nM in a scratch-wound cell-migration assay. It inhibits proliferation of MCF7 cells at higher concentrations. At typical screening concentrations, SRC as well as other SRC family kinases may be inhibited (YES1, LYN, LCK, HCK, FYN, FRK, FGR, BLK). The compound has good water solubility, drug metabolism and pharmacokinetics properties, and oral bioavailability. In vivo, in zebrafish embryos, eCF506 halts SRC-associated neuromast migration. No cardiotoxicity was observed in zebrafish. eCF506 demonstrated in vivo SRC inhibition in a xenograft model of HCT116 cells in mice.

IC₅₀ values of 5 nM or less were observed for the 9 SRC family kinases included (BLK, FGR, FRK, FYN, HCK, LCK, LYN, SRC, and YES); there are two additional SRC family members, SRM and BRK, that were not included. Thus, from the currently available data, eCF506 might be considered a probe for SRC family, not just SRC itself. Unfortunately, although it demonstrates remarkable selectivity over ABL, it has only been evaluated against 5 total kinases outside of the SRC family. The compound has favorable physical properties and is amenable to in vivo usage, but its utility is limited by restricted selectivity information.

eCF506 is a potent and selective inhibitor for the SFK family of kinases. Although it claims to be selective towards SCR proto-oncogene tyrosine-kinase, it showed the same potency than for other SFK members (IC₅₀ 0.5-5.4 nM for YES, LCK, LYN, FGR, etc). However, it is highly selective toward Abelson (ABL) Tyrosine Kinase (950 –fold), but a wider kinase profiling should be screened. The studies probed showed that the compound is a Type I kinase inhibitor, with potent antiproliferative properties and with proof of stopping MDA-MD-231 cell migration. The probe showed good physicochemical properties and good DMPK profiling, being suitable to use in cells (10-100 nM) and in in vivo models (100 nM-500 uM).