(R)-Crizotinib

(R)-Crizotinib is a dual inhibitor of c-Met and anaplastic lymphoma kinase (ALK; IC₅₀s = 8 and 20 nM, respectively, in a cell-based assay).¹ It is selective for c-Met and ALK over several other receptor- and non-receptor tyrosine kinases, including Ron, Tie2, Abl, LCK, and VEGFR2 (IC₅₀s = 0.08, 0.448, 1.159, 2.741, and >10 µM, respectively). (R)-Crizotinib selectively inhibits the proliferation of cancer cell lines with MET amplifications over cancer cell lines with MET or EGFR mutations (IC₅₀s = 5-10, 472-1,284, and 767-787 nM, respectively).² It induces apoptosis in MET-amplified EBC-1 and NCI H1993 lung cancer cells when used at a concentration of 100 nM. (R)-Crizotinib (25 mg/kg) reduces tumor volume in an EBC-1 mouse xenograft model. Formulations containing crizotinib have been used in the treatment of metastatic, relapsed, or refractory ALK-positive cancers.

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1. Cui, J.J., Tran-Dubé, M., Shen, H., 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. 54(18), 6342-6363 (2011).

2. Tanizaki, J., Okamoto, I., Okamoto, K., 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. 6(10), 1624-1631 (2011).