Crizotinib(PF-02341066) Inhibitor CAS No. 877399-52-5

Product Name	Crizotinib(PF-02341066)
Synonyms	XALKORI, PF-02341066
CAS No.	877399-52-5
Molecular Weight	450.33
Formula	C₂₁H₂₂Cl₂FN₅O
Chemical Name	3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine
Smiles	c1(c(cc(cn1)c1cnn(c1)C1CCNCC1)O[C@H](C)c1c(c(ccc1Cl)F)Cl)N
Chemical Structure

Biological activities

Crizotinib is a potent and selective dual inhibitor of mesenchymal??pithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). Crizotinib inhibit c-MET and ALK with IC50 values of 8 and 20 nM, respectively. The Ki of crizotinib for c-Met is 2 nM. ^[1] Crizotinib inhibits the catalytic activity of c-Met kinase in an ATP-competitive manner. Crizotinib exhibits improved or similar activity against NIH3T3 cells engineered to express c-Met ATP-binding site mutants V1092I or H1094R or the P-loop mutant M1250T, with IC50 values of 19, 20, and 15 nM, respectively, compared with NIH3T3 cells expressing wild-type receptor with an IC50 of 13 nM. In contrast, a marked shift in potency is observed against cells engineered to express c-Met activation loop mutants Y1230C and Y1235D with 127 and 92 nM, respectively, compared with wild-type receptor. Crizotinib also potently inhibits c-Met phosphorylation in NCI-H69 and HOP92 cells, with IC50 values of 13 and 16 nM, respectively. Crizotinib not only inhibits human GTL-16 gastric carcinoma cell growth with an IC50 of 9.7 nM, but also induces apoptosis in GTL-16 cells with an IC50 of 8.4 nM. Crizotinib prevents HGF-stimulated (Hepatocyte growth factor) human NCI-H441 lung carcinoma cell migration and invasion with IC50s of 11 and 6.1 nM, respectively. Crizotinib inhibits MDCK cell scattering with an IC50 of 16 nM. In studies done using HUVEC, Crizotinib inhibits HGF-stimulated c-Met phosphorylation, cell survival, and Matrigel invasion with IC50 values of 11, 14 and 35 nM, respectively. In addition, crizotinib inhibits serum-stimulated HMVEC branching tubulogenesis (formation of vascular tubes) in fibrin gels.^[2] Crizotinib down-regulates that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification.^[3] In the GTL-16 model, crizotinib reveals the ability to cause marked regression of large established tumors (>600 mm³) in both the 50 and 75 mg/kg/day treatment cohorts, with a 60% decrease in mean tumor volume over the 43-day administration schedule.^[2]

References

[1] Cui JJ, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011, 54(18): 6342-6363. [2] Zou HY, et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007, 67(9): 4408-4417. [3] Tanizaki J,et al. MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations. J Thorac Oncol. 2011, 6(10): 1624-1631.

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