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Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins

Kang, Chung Hyo, Yun, Jeong In, Lee, Kwangho, Lee, Chong Ock, Lee, Heung Kyoung, Yun, Chang-Soo, Hwang, Jong Yeon, Cho, Sung Yun, Jung, Heejung, Kim, Pilho, Ha, Jae Du, Jeon, Jeong Hee, Choi, Sang Un, Jeong, Hye Gwang, Kim, Hyoung Rae, Park, Chi Hoon
Biochemical and biophysical research communications 2015 v.464 pp. 762-767
apoptosis, cell communication, mutants, neoplasm cells, neoplasms, patients, proteins
Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151_L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15–20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants.