(S)-Crizotinib

(S)-Crizotinib is the S-enantiomer of Crizotinib. The approved Pfizer medicine Xalkori contains the R-enantiomer, which inhibits ALK, MET, and ROS1, whereas the S-form has been characterized primarily as an MTH1/NUDT1 inhibitor. Both have the formula C21H22Cl2FN5O; the (S)-Crizotinib molecular weight is 450.34 g/mol. CAS 1374356-45-2 specifies the active S-enantiomer, which retains strong binding affinity for MTH1 while showing significantly reduced activity against ALK, MET, and ROS1 compared to its R-counterpart. 

Application of (S)-Crizotinib

(S)-Crizotinib is used to investigate MTH1 activity, oxidized nucleotide metabolism, and responses to oxidative stress. As a stereochemical control, comparison with R-Crizotinib helps distinguish MTH1-related observations from ALK-, MET-, or ROS1-associated effects. Cellular toxicity should not be assigned to MTH1 without target-engagement or rescue experiments, because MTH1-independent effects occur in some cancer models.

In Vitro

In a cell-free assay containing 100 μM dGTP, (S)-Crizotinib inhibited MTH1 with an IC50 of 72 nM, versus 1,375 nM for R-Crizotinib. Isothermal titration calorimetry gave a Kd of 48 nM and approximately 16-fold stronger binding for the S-form. At near-Km concentrations of 8-oxo-dGTP and 2-OH-dATP, IC50 values were 330 and 408 nM, respectively.

In SW480 cells, treatment increased 53BP1 foci, ATM autophosphorylation, and DNA single-strand breaks; MTH1 overexpression reduced the strand-break response. Studies in lung and gastric cancer cells found ROS-dependent cytotoxicity despite altered MTH1 expression, showing that the cellular mechanism varies by model.

In Vivo

In SW480 xenografts, daily (S)-Crizotinib impaired tumor progression, whereas R-Crizotinib did not. Activity was reported at 25 mg/kg subcutaneously and 50 mg/kg orally, with tumor volume reduced by more than 50% in the oral comparison. These findings are model-specific. Although the search phrase Pfizer (S)-Crizotinib is used, Pfizer's approved product is the R-enantiomer; the S-form is an unapproved research compound.

Biochemical and Physiological Actions

MTH1 hydrolyzes oxidized purine nucleoside triphosphates, limiting their incorporation into nucleic acids. The (S)-Crizotinib molecular structure fits the MTH1 active site more favorably than the R-enantiomer and inhibits this sanitizing reaction. Accumulation of oxidized substrates was proposed to promote DNA damage. Because this mechanism is not universal across cell types, biochemical inhibition and antiproliferative activity should be assessed separately.

Features and Benefits of (S)-Crizotinib

• Nanomolar MTH1 inhibition measured with several nucleotide substrates.
• Enantiomeric control for separating MTH1 pharmacology from R-Crizotinib kinase activity.
• Defined (S)-Crizotinib chemical structure suitable for stereoselectivity studies.
• Published biochemical, cellular, and SW480 xenograft data with recognized mechanistic limitations.

Before use, confirm the (S)-Crizotinib structure, identity, purity, and enantiomeric excess against the product-specific certificate of analysis.