title: Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans.
abstract: Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of 11 (PF-06651600), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to its evaluation in several human clinical studies.
authors.forename: Atli
authors.identifier: 0000-0002-6791-5809
authors.initials: A
authors.lastname: Thorarensen
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 1 Burtt Road, Andover, Massachusetts 01810, United States.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Banker
authors.forename: Brian
authors.initials: B
authors.lastname: Juba
authors.forename: Jason
authors.initials: J
authors.lastname: Jussif
authors.forename: Tsung
authors.initials: T
authors.lastname: Lin
authors.forename: Fabien
authors.initials: F
authors.lastname: Vincent
authors.forename: Robert M
authors.initials: RM
authors.lastname: Czerwinski
authors.forename: Agustin
authors.initials: A
authors.lastname: Casimiro-Garcia
authors.forename: Ray
authors.initials: R
authors.lastname: Unwalla
authors.forename: John I
authors.initials: JI
authors.lastname: Trujillo
authors.forename: Sidney
authors.initials: S
authors.lastname: Liang
authors.forename: Paul
authors.initials: P
authors.lastname: Balbo
authors.forename: Ye
authors.initials: Y
authors.lastname: Che
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.forename: Matthew
authors.initials: M
authors.lastname: Hayward
authors.forename: Justin
authors.initials: J
authors.lastname: Montgomery
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 1 Burtt Road, Andover, Massachusetts 01810, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Leung
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D , 1 Burtt Road, Andover, Massachusetts 01810, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.forename: Sarah
authors.initials: S
authors.lastname: Soucy
authors.forename: Martin
authors.initials: M
authors.lastname: Hegen
authors.forename: Jotham
authors.initials: J
authors.lastname: Coe
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.forename: Felix
authors.initials: F
authors.lastname: Vajdos
authors.forename: Jill
authors.initials: J
authors.lastname: Chrencik
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
mesh_terms: D000284:Administration, Oral; D015195:Drug Design; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C000614924:PF-06651600; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D053616:Janus Kinase 3