MSC778

MSC778 is a potent FEN1 nuclease inhibitor, as validated by a range of biochemical and biophysical assays (endonuclease activity and SPR). Extensive SAR supports this conclusion, as well as the availability of a chiral, less potent negative control compound. MSC778 also shows good selectivity towards many other nucleases (> 145 fold vs EXO1, > 516 fold vs GEN1, and > 65 fold vs XPG). In addition, MSC778 has been demonstrated through a range of assays to have good cellular target engagement and on-target activity, at concentrations < 1 uM (e.g. NanoBRET and CETSA for target engagement, and inhibition of BRCA2 KO cell viability). This probe is recommended for use in cells, however it remains to be seen what the appropriate concentration is for animal studies. The efficacy data 100 mg/kg of MSC778 delivered orally in combination with Niraparib to mice with xenografts looks promising, however, as well as solid pharmacokinetic properties (T1/2 > 3 h, solubility > 400 uM, F(P/O) > 15%).