Development of ITCH-activating IRAK4 degraders as dual-targeting drug candidates for the treatment of rheumatoid arthritis

白细胞介素-1受体激活激酶4（IRAK 4）是一种丝氨酸/苏氨酸激酶，介导先天性免疫应答， 和炎症反应;它在许多细胞类型中表达。IRAKs是炎症反应的关键调节因子 Toll样受体（TLR）、白介素-1受体（IL-1 R）和白介素-18受体（IL-18 R）引发的信号传导。 在与TLR结合后，IRAK 4二聚化并结合MyD 88衔接蛋白以形成促进MyD 88与TLR结合的复合物。 IRAK自身磷酸化和活化。反过来，NF κ B和MAPK通路被激活。活化的NFkB 转录因子调节几种促炎细胞因子，包括IL-6和IL-10。IRAK 4对于 小鼠和人的抗炎反应，如用敲除/敲入小鼠的实验中所示。IRAK4 敲除小鼠对败血性休克具有抵抗力，它们的细胞因子产生受损，而IRAK 4激酶死亡 敲入小鼠在TLR激动剂攻击时产生细胞因子的能力受损。因此，抑制 IRAK 4被视为治疗以先天免疫过度激活为特征的病症的治疗途径 或炎症途径，例如，类风湿性关节炎（RA）或系统性红斑狼疮（SLE）。几个IRAK 4 抑制剂已在临床前模型中显示出抗炎作用，并且少数处于临床试验中用于治疗 类风湿性关节炎系统性红斑狼疮和牛皮癣使用称为PROTAC的异型双功能分子进行靶向蛋白质降解， 由靶蛋白结合剂与泛素E3连接酶结合剂连接组成，是一种有前途的新的 治疗方式PROTAC通过E3介导的降解去除细胞中的所有靶蛋白，因此 比简单的药理学抑制剂更有效，后者可以使一些靶分子保持完整， 变得容易受到抵抗。它们具有令人印象深刻的临床前特征，其中一些正在进行临床试验， 癌已经报道了简单的IRAK 4抑制剂，有三项临床试验。一种PROTAC， 采用E3连接酶cereblon的IRAK 4处于皮炎和化脓性汗腺炎的I期临床试验中。在 Progenra将使用不同的E3连接酶ITCH开发一种新型IRAK-4 PROTAC;它将 与Cereblon相比，具有更好的药理和治疗效果，应用更广泛， PROTAC和应该是上级的药理学抑制剂。ITCH-IRAK分子设计用于降解 IRAK 4将在体外被有效地合成并进行生物化学和生物药理学表征，并且细胞证明 将使用炎症的相关细胞模型来证明概念。化学优化及其他 临床前开发方面将在II期进行。

The interleukin-1 receptor-activated kinase 4 (IRAK4) is a serine/threonine kinase mediating the innate immune and inflammatory response; it is expressed in numerous cell types. IRAKs are key regulators of inflammatory signaling elicited by Toll-like receptors (TLRs), interleukin-1 receptor (IL-1R) and interleukin-18 receptor (IL18R). Upon binding to the TLR, IRAK4 dimerizes and binds MyD88 adaptor protein to form a complex that facilitates IRAK autophosphorylation and activation. In turn, the NFkB and MAPK pathways are activated. Activated NFkB transcription factor regulates several proinflammatory cytokines, including IL-6 and IL-10. IRAK4 is critical to murine and human anti-inflammatory responses, as shown in experiments with knockout/knockin mice. IRAK4 knockout mice are resistant to septic shock, and their cytokine production is impaired, while IRAK4 kinase-dead knock-in mice are impaired in their ability to produce cytokines upon TLR agonist challenge. Thus, inhibition of IRAK4 is seen as a therapeutic avenue for treating conditions characterized by overactivation of innate immunity or inflammatory pathways, e.g., rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Several IRAK4 inhibitors have shown anti-inflammatory effects in preclinical models, and a few are in clinical trial for treatment of RA, SLE, and psoriasis. Targeted protein degradation using heterobifunctional molecules called PROTACs, which are composed of a target protein binder tethered to a ubiquitin E3 ligase binder, is a promising new therapeutic modality. PROTACs remove all the target protein in the cell by E3- directed degradation, and thus are more efficacious than simple pharmacological inhibitors, which can leave some target molecules intact or become susceptible to resistance. They have impressive preclinical profiles, and several are in clinical trial for cancer. Simple IRAK4 inhibitors have been reported, with three reaching clinical trials. A PROTAC that degrades IRAK4 employing the E3 ligase cereblon is in Phase I clinical trial for dermatitis and hidradenitis suppurativa. In the proposed project, Progenra will develop a novel IRAK-4 PROTAC using a different E3 ligase, ITCH; it will have improved pharmacology and therapeutic efficacy with broader applications, compared with the cereblon PROTAC and should be superior to the pharmacological inhibitors. ITCH-IRAK molecules designed to degrade IRAK4 efficiently will be synthesized and characterized biochemically and biophysically in vitro, and cellular proof of concept will be demonstrated using relevant cell models of inflammation. Chemical optimization and other aspects of preclinical development will be conducted in Phase II.