title: Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
abstract: Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
authors.affiliation: Discovery Chemistry, Hoffmann-La Roche, pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, USA. stephen.lynch@roche.com
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lynch
authors.forename: Javier
authors.initials: J
authors.lastname: DeVicente
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Hermann
authors.forename: Saul
authors.initials: S
authors.lastname: Jaime-Figueroa
authors.forename: Sue
authors.initials: S
authors.lastname: Jin
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Hongju
authors.initials: H
authors.lastname: Li
authors.forename: Allen
authors.initials: A
authors.lastname: Lovey
authors.forename: John
authors.initials: J
authors.lastname: Menke
authors.forename: Linghao
authors.initials: L
authors.lastname: Niu
authors.forename: Vaishali
authors.initials: V
authors.lastname: Patel
authors.forename: Douglas
authors.initials: D
authors.lastname: Roy
authors.forename: Michael
authors.initials: M
authors.lastname: Soth
authors.forename: Sandra
authors.initials: S
authors.lastname: Steiner
authors.forename: Parcharee
authors.initials: P
authors.lastname: Tivitmahaisoon
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
authors.forename: Calvin
authors.initials: C
authors.lastname: Yee
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D007191:Indazoles / Q000737:chemistry; 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; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3