title: Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors.
abstract: As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6 μM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50=160 nM) which was co-crystallized with JNK1 to identify key molecular interactions. Kinase profiling against 125+ kinases revealed AX13587 was an inhibitor of JNK, MAST3, and MAST4 whereas its methylene homolog AX14373 (native JNK1 IC50=47 nM) was a highly specific JNK inhibitor.
authors.affiliation: ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.forename: Oana M
authors.initials: OM
authors.lastname: Cociorva
authors.forename: Tyzoon
authors.initials: T
authors.lastname: Nomanbhoy
authors.forename: Helge
authors.initials: H
authors.lastname: Weissig
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Kai
authors.initials: K
authors.lastname: Nakamura
authors.forename: Marek
authors.initials: M
authors.lastname: Liyanage
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Zhang
authors.forename: Ann Y
authors.initials: AY
authors.lastname: Shih
authors.forename: Arwin
authors.initials: A
authors.lastname: Aban
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.forename: Julia
authors.initials: J
authors.lastname: Cajica
authors.forename: Lan
authors.initials: L
authors.lastname: Pham
authors.forename: John W
authors.initials: JW
authors.lastname: Kozarich
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Shreder
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D011994:Recombinant Proteins; C587420:imidazo(1,2-a)quinoxalin-4-amine; D048055:Mitogen-Activated Protein Kinase 8
keywords: AX13587; AX14373; Imidazo[1,2-a]quinoxalin-4-amine; JNK1 inhibitor; Kinase profiling