title: Linear propargylic alcohol functionality attached to the indazole-7-carboxamide as a JAK1-specific linear probe group.
abstract: Selective inhibition of JAK1 has recently been proposed as an appropriate therapeutic rationale for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). In this study, through pairwise comparison and 3D alignment of the JAK isozyme structures bound to the same inhibitor molecule, we reasoned that an alkynol functionality would serve as an isozyme-specific probe group, which would enable the resulting inhibitor to differentiate the ATP-binding site of JAK1 from those of other isozymes. The 3-alkynolyl-5-(4'-indazolyl)indazole-7-carboxamide derivatives were thus prepared, and in vitro evaluation of their inhibitory activity against the JAK isozymes revealed that the propargyl alcohol functionality endowed the 5-(4'-indazolyl)indazole-7-carboxamide scaffold with JAK1 selectivity over other JAK isozymes, particularly JAK2.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Heerim
authors.initials: H
authors.lastname: Shin
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Seo Young
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea. Electronic address: chongy@konkuk.ac.kr.
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000480:Alkynes / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D007191:Indazoles / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D020005:Propanols / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D007191:Indazoles; D007527:Isoenzymes; D020005:Propanols; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C028255:propargyl alcohol; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2
keywords: Isozyme-specificity; Janus kinase (JAK); Probe group; Propargylic alcohol