title: A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.
abstract: Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ferguson
authors.affiliation: Department of Chemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Delgado
authors.affiliation: Department of Chemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Veronique
authors.initials: V
authors.lastname: Plantevin-Krenitsky
authors.affiliation: Department of Tumor Cell Biology, Pfizer Corporation, San Diego, California, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jensen-Pergakes
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bates
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Sanaa
authors.initials: S
authors.lastname: Torres
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Celeridad
authors.affiliation: Department of Pharmacology, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Kelven
authors.initials: K
authors.lastname: Burnett
authors.affiliation: Department of Chemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nadolny
authors.affiliation: Department of Chemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Lida
authors.initials: L
authors.lastname: Tehrani
authors.affiliation: Department of Chemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Garrick
authors.initials: G
authors.lastname: Packard
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Barbra
authors.initials: B
authors.lastname: Pagarigan
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Haelewyn
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Trish
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Frans
authors.initials: F
authors.lastname: Baculi
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Department of Corporate Planning and Strategy, Kissei Pharmaceutical Company, Matsumoto City, Nagano, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Pilgrim
authors.initials: P
authors.lastname: Jackson
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Chamberlain
authors.affiliation: Department of Biochemistry, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Laurie
authors.initials: L
authors.lastname: LeBrun
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Weilin
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Inflammation Research, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Brydon
authors.initials: B
authors.lastname: Bennett
authors.affiliation: Department of Pharmacology, Celgene Corporation, San Diego, California, United States of America.
authors.forename: Kate
authors.initials: K
authors.lastname: Blease
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D001491:Basophils / Q000166:cytology; D002460:Cell Line; D003094:Collagen / Q000737:chemistry; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000473:pathology; D004804:Eosinophils / Q000166:cytology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007191:Indazoles / Q000737:chemistry*; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D009503:Neutropenia / Q000188:drug therapy; D009504:Neutrophils / Q000166:cytology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000737:chemistry; D012867:Skin / Q000473:pathology; D000072377:Syk Kinase; D014230:Triazoles / Q000737:chemistry*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: C000609094:CC-509; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D011961:Receptors, Fc; D014230:Triazoles; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat