title: Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins.
abstract: 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.
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Chung Hyo
authors.initials: CH
authors.lastname: Kang
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
authors.forename: Jeong In
authors.initials: JI
authors.lastname: Yun
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Kwangho
authors.initials: K
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
authors.forename: Chong Ock
authors.initials: CO
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
authors.forename: Heung Kyoung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Yun
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Heejung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
authors.forename: Sang Un
authors.initials: SU
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea. Electronic address: hyungrk@krict.re.kr.
authors.forename: Hyoung Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea; Medicinal & Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: chpark@krict.re.kr.
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Park
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; D050505:Mutant Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: ALK mutants; EML4-ALK; G1/S arrest; H3122; Newly synthesized ALK inhibitor