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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.