title: Replacing the terminal piperidine in ceritinib with aliphatic amines confers activities against crizotinib-resistant mutants including G1202R.
abstract: The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC50of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues.
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Gangadhar Rao
authors.initials: GR
authors.lastname: Mathi
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.
authors.forename: Chung Hyo
authors.initials: CH
authors.lastname: Kang
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Heung Kyoung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Achary
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; College of Pharmacy, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Ha-Yeon
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Park
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Chong Ock
authors.initials: CO
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Chang-Soo
authors.initials: CS
authors.lastname: Yun
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South 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, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea. Electronic address: pkim@krict.re.kr.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
mesh_terms: D000588:Amines / Q000737:chemistry; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D051379:Mice; D009154:Mutation; D010880:Piperidines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects* / Q000235:genetics; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000588:Amines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C032727:piperidine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib
keywords: Anaplastic lymphoma kinase (ALK); Ceritinib; Crizotinib-resistant; G1202R; Non-small cell lung cancer (NSCLC)