Achary Raghavendra, Yun Jeong In, Park Chi Min, Mathi Gangadhar Rao, Lee Joo Yun, Ha Jae Du, Chae Chong Hak, Ahn Sunjoo, Park Chi Hoon, Lee Chong Ock, Hwang Jong Yeon, Yun Chang-Soo, Jung Hee Jung, Cho Sung Yun, Kim Hyoung Rae, Kim Pilho
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
Bioorg Med Chem. 2016 Jan 15;24(2):207-19. doi: 10.1016/j.bmc.2015.12.004. Epub 2015 Dec 7.
Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.
用四氢异喹啉（THIQs）对LDK378中嘧啶的二位侧链进行探索，发现8和17是高效的ALK抑制剂。THIQs 8和17在体外和体内异种移植实验中显示出令人鼓舞的效果，与LDK378相当。尽管所制备的THIQ类似物（8a - o和17a - i）活性不如其母体化合物，但8和17对包括G1202R在内的各种ALK突变酶均具有显著的抑制活性，这表明该系列化合物可进一步优化，成为克服克唑替尼和LDK378耐药问题的有用的ALK抑制剂。
