title: Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.
abstract: While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
authors.affiliation: Vertex Pharmaceuticals (Canada) Inc. , 275 Armand-Frappier, Laval, Québec H7V 4A7, Canada.
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Farmer
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Ledeboer
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoock
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Arnost
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Randy S
authors.initials: RS
authors.lastname: Bethiel
authors.affiliation: Vertex Pharmaceuticals (Canada) Inc. , 275 Armand-Frappier, Laval, Québec H7V 4A7, Canada.
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Black
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Brummel
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Ananthsrinivas
authors.initials: A
authors.lastname: Chakilam
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Warren A
authors.initials: WA
authors.lastname: Dorsch
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Fan
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Cochran
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Summer
authors.initials: S
authors.lastname: Halas
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Edmund M
authors.initials: EM
authors.lastname: Harrington
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: James K
authors.initials: JK
authors.lastname: Hogan
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: David
authors.initials: D
authors.lastname: Howe
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dylan H
authors.initials: DH
authors.lastname: Jacobs
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Leena M
authors.initials: LM
authors.lastname: Laitinen
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Shengkai
authors.initials: S
authors.lastname: Liao
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Valerie
authors.initials: V
authors.lastname: Marone
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martinez-Botella
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: McCarthy
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: David
authors.initials: D
authors.lastname: Messersmith
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Namchuk
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Luke
authors.initials: L
authors.lastname: Oh
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Penney
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Pierce
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Raybuck
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Rugg
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Saxena
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Shannon
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dina
authors.initials: D
authors.lastname: Shlyakter
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Lora
authors.initials: L
authors.lastname: Swenson
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Shi-Kai
authors.initials: SK
authors.lastname: Tian
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Town
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: M Woods
authors.initials: MW
authors.lastname: Wannamaker
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Winquist
authors.affiliation: Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Harmon J
authors.initials: HJ
authors.lastname: Zuccola
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002460:Cell Line; D062126:Databases, Chemical; D004285:Dogs; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology; D000882:Haplorhini; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000596981:2-((2-(1H-pyrrolo(2,3-b)pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide; D006574:Heterocyclic Compounds, 2-Ring; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D014633:Valine