title: Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity.
abstract: The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Dudhgaonkar
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Sourabh
authors.identifier: 0000-0003-4242-8542
authors.initials: S
authors.lastname: Ranade
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Jignesh
authors.identifier: 0000-0003-3883-6447
authors.initials: J
authors.lastname: Nagar
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Siva
authors.initials: S
authors.lastname: Subramani
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Durga Shiv
authors.initials: DS
authors.lastname: Prasad
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Preethi
authors.identifier: 0000-0003-1746-5886
authors.initials: P
authors.lastname: Karunanithi
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Ratika
authors.identifier: 0000-0001-6308-553X
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Kamala
authors.initials: K
authors.lastname: Venkatesh
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Sabariya
authors.initials: S
authors.lastname: Selvam
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Prasad
authors.identifier: 0000-0002-8209-130X
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: T Thanga
authors.initials: TT
authors.lastname: Mariappan
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.affiliation: Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: Dawn K
authors.identifier: 0000-0002-7582-849X
authors.initials: DK
authors.lastname: Stetsko
authors.affiliation: Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Holloway
authors.affiliation: Lead Evaluation, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Translational Technologies, Bristol-Myers Squibb, Hopewell, NJ 08525.
authors.forename: Jun
authors.identifier: 0000-0002-9176-6786
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Translational Technologies, Bristol-Myers Squibb, Hopewell, NJ 08525.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Yang
authors.affiliation: Discovery Toxicology, Bristol-Myers Squibb, Princeton, NJ 08543; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ruepp
authors.affiliation: Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
authors.forename: Satheesh
authors.initials: S
authors.lastname: Nair
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: Joseph
authors.initials: J
authors.lastname: Santella
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: John
authors.initials: J
authors.lastname: Duncia
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: John
authors.initials: J
authors.lastname: Hynes
authors.affiliation: Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543; julie.carman@bms.com.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Carman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011239:Prednisolone / Q000627:therapeutic use*; D051199:Toll-Like Receptor 7 / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000502:physiology
chemical_list: D053594:Myeloid Differentiation Factor 88; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D011239:Prednisolone; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases