Name: (S)-Crizotinib
Price: 255.00 USD

- Overview
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    Background
    
    (S)-crizotinibthe selectively inhibited MTH1 catalytic activity with IC50 of 72 nM, while clinically used (R)-enantiomer of the drug was inactive with IC50 of 1375 nM. Furthermore, direct-binding assays (ITC) indicated a 16-fold higher affinity of the (S)-enantiomer towards MTH1 compared with (R)-enantiomer. By using Km concentrations of substrates, the average IC50 values for (S)-crizotinib and the MTH1 substrates 8-oxo-dGTP and 2-OH-dATP were 330 nM and 408 nM respectively. (S)-crizotinib efficiently inhibited colony formation of SW480 cells andKRAS-mutated PANC1 cells, similar to SCH51344. In addition, in vitro Kd measurements indicated that (S)-crizotinib was considerably less potent than the (R)-enantiomer against the established targets ALK,MET and ROS1. (S)-crizotinib did not lead to the detection of any significant effects on proliferation in SW480 cells and showed highest toxicity towards the SV40T and KRASV12 cells. (S)-crizotinib, in contrast to (R)-crizotinib, efficiently stabilized MTH1 validating the differential targeting within BJ-KRASV12 cells using a cellular thermal shift assay. (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models as a result of disruption of nucleotide pool homeostasis via MTH1 inhibition.
    In vivo mouse xenograft studies showed (S)-crizotinib, but not the (R)-enantiomer, was able to impair overall tumour progression aswell as specifically reduce tumour volume by more than 50%.
    
    1. Huber KVM, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. NATURE,2014;508:222-227
- Properties
  - Alternative Name
    
    3-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
    
    CAS Number
    
    877399-52-5;1374356-45-2
    
    Molecular Formula
    
    C21H22Cl2FN5O
    
    Molecular Weight
    
    450.34
    
    Appearance
    
    A solid
    
    Purity
    
    99.05%
    
    Solubility
    
    ≥33.33 mg/mL in DMSO; insoluble in H2O; ≥8.58 mg/mL in EtOH with ultrasonic
    
    Storage
    
    Store at -20°C
    
    * For Research Use Only
- Reference
  - 1. Lisa A.McPhersona, Clara I.Troccolibc, et al. "Increased MTH1-specific 8-oxodGTPase activity is a hallmark of cancer in colon, lung and pancreatic tissue." DNA Repair. Available online 5 July 2019, 102644.
    2. Qing X, Shao Z, et al. "Anticancer effect of (S)-crizotinib on osteosarcoma cells by targeting MTH1 and activating reactive oxygen species." Anticancer Drugs. 2018 Apr;29(4):341-352. PMID:29420337
    3. Stewart E, Federico SM, et al. "Orthotopic patient-derived xenografts of paediatric solid tumours." Nature. 2017 Sep 7;549(7670):96-100. PMID:28854174
    4. Kawamura T, Kawatani M, et al. "Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival." Sci Rep. 2016 May 23;6:26521. PMID:27210421
    5. J Adachi, et al. "Proteome-wide discovery of unknown ATP-binding proteins and kinase inhibitor target proteins using an ATP probe." J Proteome Res. 2014 Sep 17. PMID:25230287

(S)-Crizotinib

(S)-Crizotinib

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