(S)-Crizotinib

(S)-crizotinib is a low nanomolar inhibitor of 7,8-dihydro-8-oxoguanine triphosphatase (MTH1 or NUDT1) whereas the (R)-enantiomer shows IC₅₀ values in the micromolar range. MTH1 aids in RAS-transformed cells to overcome oncogene-induced senescence by preventing reactive oxygen species (ROS)-induced DNA damage. The average IC₅₀ values for (S)-crizotinib and the MTH1 substrates 8-oxo-dGTP and 2-OH-dATP is 330 nM and 408 nM respectively. In vitro Kd measurements indicate that (S)-crizotinib is considerably less potent than the (R)-enantiomer against the targets ALK, MET and ROS1. (S)-crizotinib reduces tumor volume by more than 50% in mouse xenograft studies using SW480 cells.