Dudhgaonkar Shailesh, Ranade Sourabh, Nagar Jignesh, Subramani Siva, Prasad Durga Shiv, Karunanithi Preethi, Srivastava Ratika, Venkatesh Kamala, Selvam Sabariya, Krishnamurthy Prasad, Mariappan T Thanga, Saxena Ajay, Fan Li, Stetsko Dawn K, Holloway Deborah A, Li Xin, Zhu Jun, Yang Wen-Pin, Ruepp Stefan, Nair Satheesh, Santella Joseph, Duncia John, Hynes John, McIntyre Kim W, Carman Julie A
Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, India.
Immunology Discovery, Bristol-Myers Squibb, Princeton, NJ 08543.
J Immunol. 2017 Feb 1;198(3):1308-1319. doi: 10.4049/jimmunol.1600583. Epub 2016 Dec 21.
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.
丝氨酸/苏氨酸激酶白细胞介素-1受体相关激酶（IRAK）4是先天性免疫的关键调节因子。我们已鉴定出BMS-986126，一种强效、高选择性的IRAK4激酶活性抑制剂，在体外和体内对多种依赖髓样分化因子88（MyD88）的反应均表现出等效活性。BMS-986126未能抑制MyD88非依赖性受体下游的检测，包括肿瘤坏死因子受体和Toll样受体3（TLR3）。在TLR4下游观察到的活性非常低，TLR4也可激活一条MyD88非依赖性途径。在小鼠中，该化合物抑制了注射几种不同TLR激动剂（包括TLR2、TLR7和TLR9的激动剂）所诱导的细胞因子产生。该化合物还显著抑制了局部应用TLR7激动剂咪喹莫特所诱导的皮肤炎症。BMS-986126在狼疮的MRL/lpr和NZB/NZW模型中表现出强大活性，抑制了多种致病反应。在MRL/lpr模型中，使用次优剂量的BMS-986126和泼尼松龙联合用药观察到了强大活性，提示其具有节省类固醇的活性潜力。在使用人外周血单核细胞（PBMC）进行的TLR7和TLR9诱导的干扰素靶基因表达检测中，BMS-986126也显示出与泼尼松龙的协同作用。最后，BMS-986126使用来自狼疮患者的细胞抑制了TLR7和TLR9依赖性反应，表明抑制IRAK4在治疗狼疮方面具有潜在的治疗益处。
