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

• 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
• 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

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)是一种丝氨酸/苏氨酸激酶，介导天然免疫 和炎症反应；它在多种细胞类型中表达。IRAK是炎症的关键调节因子 Toll样受体(TLRs)、白介素1受体(IL-1R)和白介素18受体(IL18R)介导的信号传导。 当IRAK4与TLR结合时，IRAK4二聚化并与MyD88接头蛋白结合，形成促进 IRAK的自动磷酸化和激活。反过来，NFkB和MAPK通路被激活。激活的NFkB 转录因子调节多种促炎细胞因子，包括IL-6和IL-10。IRAK4对于 小鼠和人类的抗炎反应，如在基因敲除/敲除小鼠的实验中所显示的。IRAK4 基因敲除的小鼠对感染性休克具有抵抗力，其细胞因子的产生受到损害，而IRAK4激酶死亡 当TLR激动剂激发时，基因敲入小鼠产生细胞因子的能力受到损害。因此，抑制 IRAK4被视为治疗以先天免疫过度激活为特征的疾病的治疗途径。 或炎症途径，如类风湿性关节炎(RA)或系统性红斑狼疮(SLE)。几个IRAK4 抑制剂已经在临床前模型中显示出抗炎作用，少数正在进行临床试验。 类风湿性关节炎、系统性红斑狼疮和牛皮癣。使用称为PROTACs的异双功能分子来定向降解蛋白质， 它们是由与泛素E3连接酶结合的靶蛋白结合物组成的，是一种有前途的新的 治疗方式。PROTAC通过E3的定向降解去除细胞中的所有目标蛋白，从而 比简单的药物抑制剂更有效，后者可以使一些靶分子保持完整或 变得易受抗拒。他们有令人印象深刻的临床前资料，有几个正在进行临床试验 癌症。简单的IRAK4抑制剂已经被报道，有三个正在进行临床试验。降级的PROTAC 使用E3连接酶Cereblon的IRAK4正在进行皮炎和化脓性汗腺炎的I期临床试验。在……里面 提议的项目Progenra将开发一种新的IRAK-4 PROTAC，使用不同的E3连接酶ITCH；它将 与脑白蛋白相比，具有更广泛的应用，从而提高了药理和治疗效果 PROTAC，应优于药理抑制剂。用于降解的瘙痒-伊拉克分子 IRAK4将在体外有效地合成并进行生化和生物物理表征，并得到细胞证明 将使用炎症的相关细胞模型来演示这一概念。化学优化和其他 临床前开发的各个方面将在第二阶段进行。