Focal adhesion kinase 1 (FAK1) is a nonreceptor tyrosine kinase that binds epidermal growth factor receptor (EGFR), vascular epidermal growth factor receptor (VEGFR), p53 and other molecules that are critical for tumor growth and progression. CEP-37440 is a potent ATP- competitive and orally active inhibitor of FAK1 with enzymatic IC50 value of 2.0 nM and cellular IC50 value of 82 nM. CEP-37440 also inhibits anaplastic lymphoma kinase (ALK) with enzymatic IC50 value of 3.1 nM and cellular IC50 of 22 nM[1]. In vitro, CEP-37440 suppressed proliferation of inflammatory breast cancer (IBC) cell lines FC-IBC02, KPL4, SUM190 and MDA-IBC03 with GI50 values of 91 nM, 900 nM, 890 nM and 1860 nM, respectively. CEP-37440 also suppressed proliferation of breast cancer (BC) cell lines MDA-MB-231, MDA-MB-468 and normal like breast epithelial cell lines MCF-12A, MCA-10A with GI50 values of 1930 nM, 1275 nM, 1516 nM and 1700 nM, respectively. CEP-37440 at concentration of 1000 nM decreased phosphor-FAK1 in IBC cell lines FC-IBC02, SUM190, and KPL4 cells after 48h of treatment. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to apoptosis, interferon signaling, and cytokines. In vivo, oral administration of CEP-37440 at 55 mg/kg twice a day for 7 weeks inhibited the SUM190, FC-IBC02, and SUM149 breast tumor xenografts in mice with the tumor growth inhibition (TGI) of 79.7%, 33% and 23%, respectively. In addition, CEP37440 inhibited the brain metastasis in the FC-IBC02 breast xenografts mice[2]. CEP-37440 was undergoing clinical development in phase I in patients with advanced or metastatic solid tumours but no preliminary data are available[3].
作用机制
CEP-37440 inhibits the activation of FAK1 by inhibiting the phosphorylation Tyr397 of FAK1[2].
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