title: PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models.
abstract: Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.
authors.affiliation: Infinity Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Winkler
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: Faia
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: DiNitto
authors.forename: Janid A
authors.initials: JA
authors.lastname: Ali
authors.forename: Kerry F
authors.initials: KF
authors.lastname: White
authors.forename: Erin E
authors.initials: EE
authors.lastname: Brophy
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Pink
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Proctor
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lussier
authors.forename: Christian M
authors.initials: CM
authors.lastname: Martin
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Hoyt
authors.forename: Bonnie
authors.initials: B
authors.lastname: Tillotson
authors.forename: Erin L
authors.initials: EL
authors.lastname: Murphy
authors.forename: Alice R
authors.initials: AR
authors.lastname: Lim
authors.forename: Brian D
authors.initials: BD
authors.lastname: Thomas
authors.forename: John R
authors.initials: JR
authors.lastname: Macdougall
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Katti A
authors.initials: KA
authors.lastname: Jessen
authors.forename: Christian C
authors.initials: CC
authors.lastname: Fritz
authors.forename: Joi L
authors.initials: JL
authors.lastname: Dunbar
authors.forename: James R
authors.initials: JR
authors.lastname: Porter
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
authors.forename: Paul S
authors.initials: PS
authors.lastname: Changelian
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D024043:Collagen Type II; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D015394:Molecular Structure; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D024043:Collagen Type II; D007546:Isoquinolines; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; C586691:duvelisib