Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy.
Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy.
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DOI：
10.1084/jem.20151074
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发表时间：
2015-12-14
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影响因子：
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通讯作者：
Staudt LM
中科院分区：
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作者：
Kelly PN;Romero DL;Yang Y;Shaffer AL 3rd;Chaudhary D;Robinson S;Miao W;Rui L;Westlin WF;Kapeller R;Staudt LM
Kelly等报道了两种高选择性和生物可利用的小分子IRAK 4抑制剂的开发，并首次显示了它们在小鼠中的自身免疫性疾病和弥漫性大B细胞淋巴瘤的特定亚组中的治疗功效。Toll样受体信号传导衔接蛋白MYD 88的病理激活是许多自身免疫性和炎性疾病状态的基础。在弥漫性大B细胞淋巴瘤（DLBCL）的活化B细胞样（ABC）亚型中，29%的病例发生致癌MYD 88 L265 P突变，使其成为该恶性肿瘤中最常见的活化突变。IRAK 4激酶几乎解释了MYD 88的所有生物学功能，突出了IRAK 4作为异常MYD 88信号传导驱动的疾病的治疗靶标。使用创新的基于结构的药物设计方法，我们报告了高选择性和生物可利用的小分子IRAK 4抑制剂ND-2158和ND-2110的开发。这些小分子抑制LPS诱导的TNF产生，减轻胶原诱导的关节炎，并阻断小鼠模型中痛风的形成。IRAK 4抑制通过下调存活信号（包括NF-κB和JAK-STAT 3途径的自分泌IL-6/IL-10参与）促进了对携带MYD 88 L265 P的ABC DLBCL系的杀伤。在ABC DLBCL异种移植物模型中，IRAK 4抑制作为单一药剂以及与布鲁顿酪氨酸激酶（BTK）抑制剂伊曲替尼或Bcl-2抑制剂ABT-199组合抑制肿瘤生长。我们的研究结果支持药理学抑制IRAK 4作为自身免疫性疾病的治疗策略，在遗传定义的ABC DLBCL群体中，以及可能依赖于异常MYD 88信号传导的其他恶性肿瘤中。
Kelly et al. report the development of two highly selective and bioavailable small molecule IRAK4 inhibitors and show for the first time their therapeutic efficacy in autoimmune disorders and in a specific subset of diffuse large B cell lymphomas in mice. Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell–like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-κB and autocrine IL-6/IL-10 engagement of the JAK–STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling.