title: The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
abstract: Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R2position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R1position were completely inactive compared with the corresponding analogues with a methyl substituted at the R1position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC50=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
authors.affiliation: Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST), 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea.
authors.forename: Kyoung Bin
authors.initials: KB
authors.lastname: Yoon
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Kim
authors.affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: You Kyoung
authors.initials: YK
authors.lastname: Chung
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: School of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Mukai
authors.affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Republic of Korea. Electronic address: syhan@gnu.ac.kr.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Han
authors.affiliation: School of Life Science, Gwangju Institute of Science and Technology (GIST), Republic of Korea. Electronic address: kohyojin@gist.ac.kr.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.affiliation: Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST), 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea; School of Life Science, Gwangju Institute of Science and Technology (GIST), Republic of Korea. Electronic address: yongchul@gist.ac.kr.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D014230:Triazoles; C527741:pyrrolopyrimidine; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3
keywords: 4-(2,5-Triazole)-pyrrolopyrimidine; JAK2; JAK2 inhibitor; JAK2V617F; STAT (signal transducer and activator of transcription)