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

开发 ITCH 激活 IRAK4 降解剂作为治疗类风湿性关节炎的双靶点候选药物

基本信息

批准号：
10545911
负责人：
Kumar Suresh
金额：
$ 25.46万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545911
关键词：
Adaptor Signaling Protein Affect Agonist Anti-Inflammatory Agents Antigens Antiinflammatory Effect Asthma Atopic Dermatitis Autoimmune Autoimmune Diseases B-Lymphocytes Binding Biochemical Biophysics Bone Resorption Cartilage Cell model Cells Chemicals Chimeric Proteins Chronic Clinical Treatment Clinical Trials Colitis Complex Data Degenerative polyarthritis Dermatitis Development Disease Drug Targeting Event Family Gene Activation Genetic Goals Hidradenitis Suppurativa Human IRAK1 gene IRAK4 gene Immune System Diseases Immune response Impairment In Vitro Inflammation Inflammatory Inflammatory Arthritis Inflammatory Response Innate Immune Response Interleukin-1 Interleukin-1 Receptors Interleukin-10 Interleukin-17 Interleukin-18 Interleukin-6 Knock-in Mouse Knock-out Knockout Mice Lead Ligands MAP Kinase Gene Mediating Medical Modality Modeling Multiprotein Complexes Mus Natural Immunity Oncology Oral Osteoclasts Pathway interactions Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phosphorylation Phosphotransferases Population Pre-Clinical Model Process Production Property Protac Protein-Serine-Threonine Kinases Proteins Psoriasis Psoriatic Arthritis Reporting Resistance Rheumatoid Arthritis Safety Septic Shock Signal Transduction Synovial Membrane Synovitis Systemic Lupus Erythematosus T-Lymphocyte TLR1 gene TNF gene Teratogens Testing Thalidomide Therapeutic Toll-Like Receptor Pathway Toll-like receptors Treatment Efficacy Woman Work arthritis therapy asthma model bone cancer clinical trial cell type chemokine comparative efficacy cytokine design dimer drug candidate experimental study improved in vivo inflammatory milieu inhibitor interleukin-18 receptor kinase inhibitor lead optimization lenalidomide macrophage multimodality novel novel therapeutics osteoclastogenesis overexpression phase 1 study pomalidomide pre-clinical preclinical development protein degradation recruit response scaffold small molecule targeted treatment transcription factor ubiquitin-protein ligase

项目摘要

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.

白介素-1受体激活的激酶4（IRAK4）是介导先天性免疫的丝氨酸/苏氨酸激酶和炎症反应；它以多种细胞类型表示。 iraks是炎症的关键调节因子通过Toll样受体（TLR），白介素-1受体（IL-1R）和白介素-18受体（IL18R）引起的信号传导。与TLR结合后，IRAK4二聚并结合MyD88适配器蛋白，形成促进的复合物 IRAK自磷酸化和激活。反过来，NFKB和MAPK途径被激活。激活的NFKB 转录因子调节几种促炎细胞因子，包括IL-6和IL-10。 irak4对如敲除/敲除小鼠的实验所示，鼠和人类的抗炎反应。 irak4 淘汰小鼠对败血性休克有抵抗力，其细胞因子的产生受损，而IRAK4激酶死亡在TLR激动剂挑战时产生细胞因子的能力受损。因此，抑制 IRAK4被视为治疗以先天免疫过度激活为特征的治疗条件的治疗途径或炎症途径，例如类风湿关节炎（RA）或全身性红斑狼疮（SLE）。几个irak4 抑制剂在临床前模型中显示出抗炎作用，其中一些正在临床试验中进行治疗 RA，SLE和牛皮癣。靶向蛋白质降解，使用称为Protacs的异功能分子，由靶蛋白粘合剂组成的靶蛋白粘合剂束缚于泛素E3连接酶粘合剂，是一种有希望的新的治疗方式。 Protac通过E3的定向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，这可以使某些目标分子完整或变得容易受到抵抗。它们具有令人印象深刻的临床前剖面，其中一些正在临床试验中癌症。据报道，简单的IRAK4抑制剂进行了三项临床试验。一个降解的protac 采用E3连接酶少数的IRAK4正在I期临床试验中皮炎和Hidradenenitis Pururativa。在拟议的项目，Gepenra将使用不同的E3连接酶（Itch）开发一种新型的Irak-4 Protac。会与Cereblon相比，具有更广泛应用的药理学和治疗功效 Protac，应该优于药理抑制剂。瘙痒 - irak分子旨在降解 irak4有效地将在体外和生物物理上合成并表征，并证明细胞概念将使用相关的炎症细胞模型来证明。化学优化和其他临床前发展的各个方面将在第二阶段进行。