Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins.
作者： Chung Hyo Kang , Jeong In Yun , Kwangho Lee , Chong Ock Lee , Heung Kyoung Lee
DOI: 10.1016/J.BBRC.2015.07.027
关键词: Crizotinib 、 Protein kinase B 、 Fusion protein 、 Apoptosis 、 ALK inhibitor 、 Biology 、 In vitro 、 Cell signaling 、 Cancer cell 、 Molecular biology
摘要: Abstract Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through wild type enzyme assay, selected two compounds, KRCA-0080 KRCA-0087, have trifluoromethyl instead of chloride in R2 position. We characterized these compounds by in vitro in vivo assays. Enzyme assay shows that is more various mutants, including L1196M, G1202R, T1151_L1152insT, C1156Y, are seen crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our downregulate cellular signaling, such as Akt Erk, suppressing activity inhibit proliferation EML4-ALK. Interestingly, induced strong G1/S arrest H3122 leading apoptosis, proved PARP-1 cleavage. In vivo xenograft found significant reduction tumor size compared crizotinib 15–20%. Conclusively, report a efficacy well excellent inhibitory mutants.
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