更新于：2024-11-01

IRAK1

更新于：2024-11-01

基本信息

别名

interleukin 1 receptor associated kinase 1、Interleukin-1 receptor-associated kinase 1、IRAK

+ [3]

简介

Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.

关联

项与 IRAK1 相关的药物

Pacritinib

帕克替尼

靶点

ALK2 x CSF-1R x FLT3 x IRAK1 x JAK2

作用机制

ALK2抑制剂 [+4]

在研机构

Swedish Orphan Biovitrum AB [+2]

原研机构

CTI BioPharma Corp.

在研适应症

原发性骨髓纤维化 [+6]

非在研适应症

急性髓性白血病 [+16]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2022-02-28

R-289

靶点

IRAK1 x IRAK4

作用机制

IRAK1拮抗剂 [+1]

在研机构

Rigel Pharmaceuticals, Inc.

原研机构

Rigel Pharmaceuticals, Inc.

在研适应症

骨髓增生异常综合征

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

R835

靶点

IRAK1 x IRAK4

作用机制

IRAK1拮抗剂 [+1]

在研机构

Rigel Pharmaceuticals, Inc.

原研机构

Rigel Pharmaceuticals, Inc.

在研适应症

自身免疫性疾病 [+1]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 IRAK1 相关的临床试验

NCT06052618 / Recruiting临床2期IIT

Phase II Study of Pacritinib in Kaposi Sarcoma Herpesvirus (KSHV)-Associated Multicentric Castleman Disease and KSHV-Associated Inflammatory Cytokine Syndrome (KICS)

Background:
Kaposi sarcoma herpesvirus (KSHV)-associated inflammatory cytokine syndrome (KICS) and KSHV-multicentric Castleman disease (MCD) occur in people living with HIV. These diseases cause severe inflammation that can be fatal if not treated.
Objective:
To test a drug (pacritinib) in people with KSHV-associated KICS or MCD.
Eligibility:
People aged 18 years and older with KSHV-associated KICS or MCD. They must have at least one symptom.
Design:
Participants will be screened. They will have a physical exam with blood tests and tests of their heart function. They will have imaging scans. Their ability to perform everyday tasks will be reviewed. In some participants who have Kaposi sarcoma (KS) with KICS or MCD, these individuals may need a bronchoscopy and/or endoscopy of the upper or lower intestine: A flexible tube with a camera and a light source will be inserted through the mouth or anus to see these structures and assess any KS.
Pacritinib is a capsule taken by mouth. Participants will take the drug twice a day, every day, for up to 24 weeks. They will write down each dose in a diary.
Participants will visit the clinic 3 times in the first 4 weeks. Their visits will taper to once every 4 weeks. Imaging scans, blood tests, and other tests will be repeated during these visits. Participants will give samples of saliva. They may opt to allow tissues samples to be taken from their skin and lymph nodes.
Participants will have follow-up visits 7 days and 30 days after their last dose of pacritinib. After that, they will visit the clinic every 3 months for up to 1 year. The physical exam and blood, heart, and imaging tests will be repeated at these visits.

开始日期2024-11-04

申办/合作机构

National Cancer Institute

NCT06303193 / Not yet recruiting临床1/2期IIT

Phase I/II Trial of Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms

Background:
Myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are blood disorders that can cause serious complications in children and adults. MDS and MDS/MPN can also progress to acute myeloid leukemia. Treatments for these disorders are risky and not always effective. Better treatments are needed.
Objective:
To test a study drug (pacritinib) in adults and children with MDS or MDS/MPN.
Eligibility:
Children (aged 12 to 17 years) and adults (aged 18 years and older) with MDS or MDS/MPN.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart function. They may have a bone marrow biopsy: An area over the hip will be numbed; a needle will be inserted to remove a sample of soft tissue from inside the hipbone.
Pacritinib is a capsule taken by mouth. All participants will take the study drug 2 times a day, every day, in 28-day cycles. They will write down the date and time they take each capsule. Doctors will assign varying dosages of the drug to different participants.
Participants will have clinic visits each week during cycle 1; every 2 weeks during cycle 2; and gradually increasing to every 3 months after cycle 13. Treatment will continue for up to 8 years.
Bone marrow biopsies, heart tests, and other tests will be repeated at intervals throughout the study. Participants will also fill out questionnaires about their quality of life, the symptoms of their disease, and other topics.

开始日期2024-11-04

申办/合作机构

National Cancer Institute

NCT06538181 / Not yet recruiting临床1期IIT

A Phase 1 Study of Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

VEXAS (vacuoles, E1 ubiqutin-activating enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described disorder with severe hematologic and rheumatologic manifestations caused by somatic variants in the ubiquitin- activating enzyme gene, UBA1, that is acquired in hematopoietic progenitor cells. Patients are often debilitated by autoinflammatory symptoms and there is currently no standard of care available. There is a clinically unmet need for better therapies in VEXAS Syndrome. There have been no prospective clinical trials of JAK-I in VEXAS syndrome. The investigators hypothesize that pacritinib, as a JAK2/IRAK1 inhibitor with a manageable safety profile in myelofibrosis patients with thrombocytopenia, will improve the autoinflammatory and hematologic manifestations of VEXAS syndrome with a tolerable toxicity profile.
The investigators propose a single arm, pilot Phase 1 study evaluating the safety and tolerability of pacritinib in patients with VEXAS syndrome with an initial safety run-in phase of 6 patients treated with pacritinib 200mg twice daily (BID) on days 1-28 of a continuous 28 day cycle. If no more than 1 patient experiences a dose-limiting toxicity (DLT), the investigators will enroll an expansion cohort to gain additional toxicity and efficacy data, for a total enrollment of 15 patients. If more than 1 patient experiences a DLT during the safety run-in phase, the investigators will decrease the dose to 100 mg BID, and if no more than 1 of 6 patients experiences a DLT, the investigators will complete the expansion cohort as above for up to a total enrollment of 15 patients. If more than 1 patient experiences a DLT at 100 mg BID, the investigators will discontinue the study. Patients will be treated for up to 12 cycles.

开始日期2024-10-31

申办/合作机构

Washington University School of Medicine

[+1]

100 项与 IRAK1 相关的临床结果

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100 项与 IRAK1 相关的转化医学

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0 项与 IRAK1 相关的专利（医药）

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1,721

项与 IRAK1 相关的文献（医药）

2025-05-01·Neural Regeneration Research

The complex effects of miR-146a in the pathogenesis of Alzheimer’s disease

Article

作者: Cui, Guohong ; Liu, Jiajia ; Guo, Haidong ; Wang, Yu ; Long, Yunfan

Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities. Neuroinflammatory plaques formed through the extracellular deposition of amyloid-β proteins, as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins, comprise two typical pathological features of Alzheimer’s disease. Besides symptomatic treatment, there are no effective therapies for delaying Alzheimer’s disease progression. MicroRNAs (miR) are small, non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes. Indeed, miR-146a, a NF-κB-regulated gene, has been extensively implicated in the development of Alzheimer’s disease through several pathways. Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder. MiR-146a is believed to reduce amyloid-β deposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway; however, there is also evidence supporting that it can promote these processes through many other pathways, thus exacerbating the pathological manifestations of Alzheimer’s disease. It has been widely reported that miR-146a mediates synaptic dysfunction, mitochondrial dysfunction, and neuronal death by targeting mRNAs encoding synaptic-related proteins, mitochondrial-related proteins, and membrane proteins, as well as other mRNAs. Regarding the impact on glial cells, miR-146a also exhibits differential effects. On one hand, it causes widespread and sustained inflammation through certain pathways, while on the other hand, it can reverse the polarization of astrocytes and microglia, alleviate neuroinflammation, and promote oligodendrocyte progenitor cell differentiation, thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons. In this review, we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer’s disease. We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer’s disease, such as amyloid-β deposition, tau protein hyperphosphorylation, neuronal death, mitochondrial dysfunction, synaptic dysfunction, and glial cell dysfunction, as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer’s disease.

2024-12-31·Emerging Microbes & Infections

Capsid protein mediated evasion of IRAK1-dependent signalling is essential to Sindbis virus neuroinvasion and virulence in mice

Article

作者: Karki, Deepa ; Landers, V Douglas ; Sokoloski, Kevin J ; Thomas, Milton ; Isom, Cierra M

ABSTRACTAlphaviruses are arthropod-borne, single-stranded positive-sense RNA viruses that are recognized as rapidly emerging pathogens. Despite being exquisitely sensitive to the effects of the innate immune response alphaviruses can readily replicate, disseminate, and induce pathogenesis in immunologically competent hosts. Nonetheless, how alphaviruses evade the induction of an innate immune response prior to viral gene expression, or in non-permissive infections, is unknown. Previously we reported the identification of a novel host/pathogen interaction between the viral Capsid (CP) protein and the host IRAK1 protein. The CP/IRAK1 interaction was determined to negatively impact IRAK1-dependent PAMP detection in vitro, however, the precise importance of the CP/IRAK1 interaction to alphaviral infection remained unknown. Here we detail the identification of the CP/IRAK1 interaction determinants of the Sindbis virus (SINV) CP protein and examine the importance of the interaction to alphaviral infection and pathogenesis in vivo using an interaction deficient mutant of the model neurotropic strain of SINV. Importantly, these interaction determinants are highly conserved across multiple Old-World alphaviruses, including Ross River virus (RRV), Mayaro virus (MAYV), Chikungunya virus (CHIKV), and Semliki Forest virus (SFV). In the absence of a functional CP/IRAK1 interaction, SINV replication is significantly restricted and fails to disseminate from the primary site of inoculation due to the induction of a robust type-I Interferon response. Altogether these data indicate that the evasion of IRAK1-dependent signalling is critical to overcoming the host innate immune response and the in vivo data presented here demonstrate the importance of the CP/IRAK1 interaction to neurovirulence and pathogenesis.

2024-12-01·International Immunopharmacology

Artemisinin attenuates perinatal inflammation and consequent oxidative stress in oligodendrocyte precursor cells by inhibiting IRAK-4 and IRAK-1

Article

作者: Sun, Junfang ; Jiang, Hong ; Ma, Shiyi ; Zhou, Yue ; Gao, Na ; Li, Yishi ; Gou, Zhixian ; Sun, Mengya ; Lai, Chunchi ; Lu, Liqun ; Liu, Jingyi ; Zhang, Feng

BACKGROUNDThe main causes of abnormal white matter development (periventricular leukomalacia) in premature infants are perinatal inflammation and the consequent oxidant/antioxidant imbalance in oligodendrocyte precursor cells (OPCs); however, the underlying mechanisms remain largely unclear. In this work, a rat model of prenatal inflammation was used to examine the mechanism by which artemisinin (ART) protects against white matter dysplasia.METHODSWe established a primary OPC model and rat model of perinatal inflammation. ART was identified from the FDA-approved medicinal chemical library to be beneficial for treating OPC inflammation in model systems. Based on bioinformatics analysis of protein interactions and molecular docking analysis, we further identified the possible targets of ART and evaluated its specific effects and the underlying molecular mechanisms in vivo and in vitro.RESULTSFollowing inflammatory stimulation, ART strongly promoted the maturation of OPCs and the development of white matter in the brain. A Cellular thermal shift assay (CETSA) demonstrated that interleukin-1 receptor-associated kinase-4 (IRAK-4) and interleukin-1 receptor-associated kinase-1 (IRAK-1) may be targets of ART, which was consistent with the findings from molecular modelling with Autodock software. Experiments conducted both in vivo and in vitro demonstrated the activation of the IRAK-4/IRAK-1/nuclear factor kappa-B (NF-κB) pathway and the production of inflammatory factors (IL-1β, IL-6, and TNF-α) in OPCs were greatly suppressed in the group treated with ART compared to the lipopolysaccharide (LPS)-treated group. Moreover, ART dramatically decreased reactive oxygen species (ROS) levels in OPCs while increasing nuclear factor e2-related factor 2 (Nrf2) levels.CONCLUSIONOur findings suggest that ART can significantly reduce OPC perinatal inflammation and consequent oxidative stress. The targeted inhibition of IRAK-4 and IRAK-1 by ART may be a potential therapeutic strategy for alleviating abnormalities in white matter development in premature newborns.

项与 IRAK1 相关的新闻（医药）

2024-09-18

·BiG生物创新社

针对炎症靶点开发治疗自免的PROTAC

作者｜小鱼摘要：诸多研究正在将与自免相关的炎症靶点和PROTAC两者相结合，比较热门的靶点是HDAC VI、IRAK3/4、PCAF、GCN5、JAK/STAT、RIPK2、STING、MIF、IKZF，针对这些靶点设计开发用于自免治疗的PROTACs，在临床前阶段显示出良好的体外效力。引言：炎症可以是自身免疫性疾病的一个触发因素，也可以是其结果。例如，类风湿性关节炎（RA）和系统性红斑狼疮（SLE）等自身免疫性疾病的发病机制中，炎症反应是关键的组成部分。此外，炎症性细胞因子如IL-1β、TNF-α和IL-6等在自身免疫性疾病的发展中起着重要作用。图1 炎症信号通路 PROTAC（Proteolysis Targeting Chimeras，蛋白降解靶向嵌合体）是一种创新的蛋白质降解技术，其结构由三部分组成：一端是与目标蛋白（POI）结合的配体，另一端是与特定的E3泛素连接酶结合的配体，中间通过一个Linker（连接子）相连。这种设计使得PROTAC分子能够同时结合目标蛋白和E3泛素连接酶，从而促进目标蛋白的泛素化，并通过泛素-蛋白酶体途径（UPS）实现目标蛋白的选择性降解。图2 PROTAC结构及作用机制通过设计特定的PROTAC分子，可以诱导与自身免疫性疾病相关的靶蛋白降解，从而为治疗这些疾病提供新的策略。在设计和评估PROTAC分子时，研究人员会关注其诱导靶蛋白降解的能力，这通常通过DC50（半最大降解浓度）和Dmax来量化。DC50是指能够导致目标蛋白降解50%的PROTAC浓度，而Dmax则表示在饱和浓度下PROTAC能实现的最大降解水平。现将HDAC VI、IRAK3/4、PCAF、GCN5、JAK/STAT、RIPK2、STING、MIF、IKZF靶点的临床前PROTACs开发情况介绍如下： 1 HDAC VI（组蛋白去乙酰化酶6）组蛋白去乙酰化酶（HDAC）是一类重要的酶，它们通过去除组蛋白上的乙酰基团来调控基因的表达。HDAC的功能异常与多种疾病的发生发展有关，尤其是癌症。阻断HDAC可导致细胞死亡和抗炎活性。用于癌症治疗的强效HDAC抑制剂，TSA（Trichostatin A）、SAHA（Suberoylanilide Hydroxamic Acid）等，可以减少诱导关节炎大鼠的肿胀、血管形成和骨侵蚀。 HDAC VI是目前与自身免疫性疾病关联最大的HDAC家族成员，负责炎症的调节，阻断HDAC VI可治疗类风湿性关节炎，以改善滑膜炎症。以下是针对HDAC V1靶点的PROTAC开发情况： Compound2：Cao等人引入了“点击”化学的概念，合成了由不同连接子长度组成的PROTAC分子。其中化合物2的体外研究显示，DC50为108.9 nM，能够显著降解HDAC VI，以及减少 IL-1β（白细胞介素-1β）的释放和p20（caspase-1的中间体片段）的产生；体内研究表明，化合物2降低IL-1β水平，而不影响TNF- α（肿瘤坏死因子-α）水平。 Compound3：Yang等人合成的PROTAC分子，以来那度胺作为配体与CRBN（E3连接酶配体）结合，DC50为1.9 nM，显著降解HDAC VI。图3 靶向HDAC VI的PROTACs 2 IRAK3/4（IL-1受体相关激酶） IRAK（Interleukin-1 receptor-associated kinase）是与IL-1R和Toll样受体（TLR）信号传导相关的一类丝氨酸-苏氨酸蛋白激酶。IRAK家族成员通过激活下游的信号转导分子如NF-κB和MAPK途径，在调节炎症反应和免疫反应中起着关键作用。其中IRAK-4尤其重要，因为它是固有免疫系统中IL-1家族和TLR家族信号通路交汇的关键节点，参与全身炎症反应的调控。IRAK4蛋白涉及类风湿关节炎和化脓性汗腺炎（HS），是目前治疗免疫疾病的深入研究课题。由于IRAK1和IRAK4的ATP结合位点之间的高度相似性，IRAK4的选择性抑制剂或可治疗系统性红斑狼疮。 Compound5、6：Kargbo等认为，PROTAC可以克服IRAK4蛋白的催化结构域高度保守的限制，开发的化合物5、6可有效降解IRAK4，IC50和DC50值低于30 nM。 Compound7、8：Nunes等人使用异喹啉弹头（IRAK4抑制剂）和各种E3配体，如VHL（VonHippel-Lindau）、CRBN或IAP（凋亡抑制剂蛋白）。其中，含有氟基团的化合物7的DC50为259 nM。进一步细化结构，化合物8采用螺旋环嘧啶连接子，比柔性的线性碳链更具刚性和极性，DC50为151 nM。 Compound9：Chen等人研究发现，采用更短长度连接子的PROTACs并没有观察到IRAK4的显著降解，而含有PEG（聚乙二醇）连接子的化合物9可以有效地降低IRAK4的水平。 Compound10：Zhang等人，将环丙基作为连接子偶联位点，化合物10抑制了IL-6的产生；接着改变连接子，合成一系列PROTACs，其中化合物10b和10d的DC50值为190 nM和405 nM。 Compound11、12：Degorce等人在研究IRAK4蛋白时，偶然发现IRAK3抑制剂治疗自免疾病的功效。POI配体采用吡咯三嗪的顺式异构体，E3连接酶配体采用VHL或CRBN。研究表明，含有PEG连接子的CRBN比VHL具有更好的降解能力，且在采用CRBN的情况下，连接子的长度与降解效果成正比。化合物11和12选择性降解IRAK3，DC50分别为0.052 μM和0.002 μM，Dmax分别为74%和98%。 Compound13：Rowley等人也做出了类似的努力，他们研究了IRAK3蛋白来控制树突状细胞介导的IL-12。采用克唑替尼作为POI配体，VHL作为E3连接酶配体，反式环己酰胺作为连接子，化合物13能够有效降解IRAK3，DC50为94 nM和 Dmax为95%。用化合物13处理树突状细胞后，无论LPS（脂多糖）存不存在，IRAK3均被降解，同时在LPS刺激下，IL-12p水平显著升高。图4 靶向IRAK3/4的PROTACs 3 PCAF和GCN5（p300/cbp相关因子和组蛋白乙酰转移酶） PCAF和GCN5是密切相关的表观遗传蛋白，在多种细胞通路中调节免疫功能。阻断PCAF和GCN5治疗自身免疫性疾病的机制是通过，减少H3K18、H3K9乙酰化，抑制NF-κB，IFN-β，TBK1过表达，调节炎症免疫信号。 Compound14：Bassi等人采用PCAF和GCN5的活性抑制剂GSK 4027作为POI配体，采用CRBN作为E3连接酶配体，化合物14能够有效降解PCAF和GCN5，DC50分别为1.5 nM，3 nM。在10 min内，浓度为30 nM的化合物14能使蛋白降解80%。图5 靶向PCAF/GCN5的PROTACs 4 JAK/STAT（Janus激酶信号转导因子/转录激活因子） JAK/STAT通路是一种重要的细胞内信号传导途径，细胞因子与JAK受体结合，启动STAT转磷酸化，导致增殖和分化等活性的基因表达，引发多种疾病，如类风湿性关节炎（RA）、阿尔茨海默病（AD）、炎症性肠病（IBD）和多发性硬化症（MS）。JAK抑制剂，如Tofacitinib、Ruxolitinib、Baricitinib等，通过调节T细胞活化和自然杀伤（NK）细胞活性，改善类风湿性关节炎。尽管JAK/STAT靶点已经发现了几十年，但其开发仍存在挑战，如药物半衰期短、血栓栓塞等副作用以及JAK/STAT通路和非典型信号转导之间的串扰。PROTACs可能是破局之选。 Compound21-26：Shah等人，以嘧啶和喹恶啉核作为POI配体。其中，喹恶啉基序的细胞渗透性优于嘧啶基序，且对JAK2具有更高的选择性，已证明6个PROTACs具有降解JAK1和JAK2的作用。 Compound28-30：Kargbo等人发现化合物28的EC50为0.0002 μM，进一步设计了含有Ruxolitinib、Baricitinib（强效JAK抑制剂）的化学物29和30，EC50分别为0.00054 μM和0.0039 μM。图6 靶向JAK/STAT的PROTACs 5 RIPK2（受体相互作用蛋白激酶2） RIPK2是一种在细胞内信号传导中起关键作用的激酶，参与调节细胞的固有免疫、适应性免疫以及凋亡过程。RIPK2的过度激活和功能失调可导致多种炎症性疾病、自身免疫疾病、癌症以及神经系统疾病。到目前为止，由于泛抑制作用，还没有可用于临床的RIPK2抑制剂。 Compound32-34：Mares等人开发了化合物32，pDC50（DC50的负对数）为9.4± 0.2，但溶解度较差。进一步，通过添加非亲脂性基团来提高溶解度，合成化合物33，pDC50为7.9。进一步，为了解决大剂量依赖性，所合成的化合物34，效力增加了10倍，pIC50为8.0。 Compound35：Bondeson等人开发的化合物35，DC50为1.4 nM，Dmax为95%。图7 靶向RIPK2的PROTACs 6 STING（人体干扰素基因刺激因子） STING是一种在固有免疫反应中起关键作用的信号转导分子，被来自病原体和宿主细胞质DNA激活后，激活促炎介质，如细胞因子和IFNs的释放来对抗细菌感染。 Compound45-50：Liu等设计了PROTACs来靶向STING途径治疗各种自身免疫疾病，如系统性红斑狼疮。POI配体为C-170 STING抑制剂，E3连接酶配体为为CRBN，合成连接子长度不同的化合物45-50。其中，化合物47显示出最令人满意的结果，DC50值为3.2 μM。在小鼠肾脏组织中的体内研究表明，化合物47可以以剂量依赖的方式降低IFNβ、IL-6和CXCL-10的水平。图8 靶向STING的PROTACs 7 MIF（巨噬细胞迁移抑制因子）虽然MIF以其抗癌潜力而闻名，但它也与免疫反应有关。 Compound51-56：在Xiao等人开发的，以7-羟基香豆素和7-羟基-3,4-二氢苯并恶嗪-2-1核为POI配体，以CRBN为E3连接酶配体的化合物51-56中，化合物54表现最优，在2 μM时，与MIF的Ki值为71%，MIF在A549细胞中降解率为71%。图9 靶向MIF的PROTACs 8 IKZF（Ikaros锌指转录因子） IKZF对免疫调节活性至关重要，其基因的多态性可导致系统性红斑狼疮。 Compound57、58：化合物57和58与CRBN-DDB1（DNA损伤结合蛋白-1）复合物属于强结合，KD值小于10 μM。图10 靶向IKZF的PROTACs 小结 PROTACs在探索自身免疫性疾病等靶点方面具有良好的体外效力。在理想情况下，研究人员希望获得高Dmax值（例如大于90%的降解效率）和低DC50值，这意味着PROTAC分子在较低浓度下就能实现高效的蛋白降解，预示着更好的治疗效果和更低的副作用。通过优化PROTAC分子的设计，包括选择合适的靶蛋白（POI）配体、E3连接酶配体和连接子（linker），提高了PROTAC分子的疗效和选择性，有望成功将PROTACs带入自免治疗的临床阶段。具体的设计有考虑到：①优化连接子长度以稳定三元配合物；②添加非亲脂性基团以增加溶解度；③POI配体只留下结合部位，其余修改为连接子，减少额外的毒性；④借助BioPROTACs和杂交PROTACs的研究进展，找到缺乏配体结合位点的POI的解决方案；⑤通过口服/静脉注射纳米制剂，持续递送药物，延长半衰期。参考资料： https://doi-org.libproxy1.nus.edu.sg/10.1039/D4MD00142G 10.12日，深圳；BiG第二届自免研讨会 8:50-8:55 领导致辞 8:55-9:00 联合主办方致辞涂欢：深圳医学科学院副院长、深圳湾实验室副主任 9:00-9:30 临床视角，创新药开发自免，如何选择适应症？徐沪济：海军军医大学长征医院大内科主任兼风湿科主任/清华大学医学院教授 9:30-10:00 药厂视角，自免布局和BD策略 10:00-10:30 MNC视角，AZ在肿瘤+自免的布局和开发策略章宇：阿斯利康产品管线和项目管理副总裁 10:30-11:30 Panel：自免创新药如何立项？MNC&biotech的布局策略，BD合作背后的故事？肖昌春：赛诺菲中国研究负责人、赛诺菲研究院负责人徐亚南：武田制药全球外部创新合作部中国区负责人靳照宇：明济生物董事长兼CEO 朱向阳：华奥泰生物总经理周潇薇：松禾资本董事总经理（主持） 11:30-12:30 Panel：从肿瘤转战自免，创新疗法（CAR-T/CAR- NK/双抗/ADC/PROTAC等）如何选择适应症，不同modality各自开发优势及挑战，在哪里？未来有哪些新靶标值得关注？范晓虎：湾岛细胞创始人/CEO 王立群：星奕昂生物创始人、董事长兼CEO 花海清：映恩生物研发副总裁冯焱：领泰生物创始人/CEO 张雷：深圳湾实验室特聘研究员卢宏韬：科望医药联合创始人/CSO、BiG总干事（主持） 12:30-14:00 午餐&参观&自由交流 ● 深圳医学科学院（SMART）、卫光生命科学园、湾有引力 14:00 论坛闭幕报名入口 PS：免费席位有限，均为审核制观众门票：0元含12日自免会议&午餐；限biotech/Pharma、临床、院校科学家、投资机构代表共建Biomedical创新生态圈！如何加入BiG会员？ ▼

蛋白降解靶向嵌合体临床结果

2024-08-28

·CPHI制药在线

靶点 | 浅谈自免疾病新靶点IRAK4进展，拜耳放弃，国内外多家药企坚守

关注并星标CPHI制药在线 IRAK是指在前炎症细胞因子白细胞介素-1（IL-1）诱导下能和白细胞介素-1受体（IL-1R）相结合的一类丝/苏氨酸激酶，家族成员包括IRAK1、IRAK2、IRAK4和IRAKM。其中IRAK1、IRAK4在TLR介导的信号通路中起正向调节作用，IRAK2、IRAKM在TLR介导的信号通路中起负向调节作用。关于IRAK4 IRAK4，全称白细胞介素1受体相关激酶4，是TLR/IL-1R介导的炎症信号转导通路下游的关键因子。TLRs /IL-1R与配体结合以后，募集MyD88分子，MyD88通过其N末端的死亡结构域进一步募集IRAK4， IRAK4通过自身磷酸化反应，发挥激酶活性，激活其底物IRAK1， IRAK1 随即磷酸化，进而活化下游丝氨酸/苏氨酸激酶TAK1，激活NF-κB及MAPK信号通路，随后产生促炎细胞因子、趋化因子和破坏性酶，最终导致产生炎症反应，介导先天性免疫。此外，研究还发现 IRAK4过表达可以增强LPS诱导的NADPH氧化酶活性，诱导下游的p38 MAPK 的信号转导（p38 MAPK通路是在转录和翻译阶段促炎细胞因子生物合成的关键调节因子）。 IRAK4靶向药进展 IRAK4被认为是炎症性疾病和自身免疫性疾病药物开发的潜力靶点，目前已有多款靶向药进入临床试验阶段，详见下表。在研IRAK4靶向药药物类型多样，除了小分子化药（如TQH3821、MY004567、BAY1834845等），还包括PROTAC降解剂（如GS-6791、BGB-45035等）。研发进度上，在研IRAK4靶向药最快进入2期临床。其中KT-474 是一种潜在首创IRAK4降解剂，被开发用于治疗TLR/IL-1R驱动的免疫炎症性疾病，如特应性皮炎、化脓性汗腺炎、类风湿性关节炎等。与靶向单一细胞因子的单克隆抗体相比，KT-474旨在更广泛地阻断TLR/IL-1R介导的炎症，通过消除 IRAK4的激酶和支架功能来实现通路抑制。 2020年7月，赛诺菲与Kymera Therapeutics达成多项目战略合作，联合开发和商业化IRAK4靶向蛋白降解疗法。2023年11月，Kymera Therapeutics宣布KT-474的1期临床试验取得积极结果：KT-474对缓解化脓性汗腺炎(HS)和特应性皮炎(AD)患者的疾病负担和症状产生了积极的作用，且在中度至重度疾病患者中观察到了全身抗炎作用。 MY004567是国内首家申报临床的IRAK4抑制剂，临床前研究显示其与同靶点临床在研药物相比，药代行为更好、药效更优。目前，MY004567针对类风湿关节炎的2期临床试验正在进行中。 BGB-45035等处于1期临床，它是百济神州基于其CDAC平台上研发的一款靶向IRAK4的蛋白降解剂。公开资料显示，BGB-45035有潜力诱导更深、更快的IRAK4降解，并比其他同类药物具有更强的细胞因子抑制作用。2024年6月，评估BGB-45035在健康受试者中单次和多次递增剂量的安全性、耐受性、药代动力学和药效学以及食物效应的1期随机研究启动。2024年8月，BGB-45035在国内获批临床，治疗中重度特应性皮炎。然而，IRAK4靶向药的开发并不顺利。拜耳在公布2024年Q1业绩时透露终止Zaberdosertib治疗特应性皮炎的2期临床（Damask研究）。BAY1834845是一款靶向IRAK4的小分子抑制剂。在健康男性受试者中进行的1期研究结果显示：BAY1834845可以显著抑制咪喹莫特乳膏诱导的皮肤炎症反应，也可以显著降低血清IL-6和TNF-α水平，并抑制C反应蛋白、降钙素原和IL-8对脂多糖诱导的炎症反应的应答。从布局企业来看，除了国内药企，多家大型跨国药企（MNC），尤其是拜耳和吉利德也看好IRAK4靶点的潜力。其中吉利德除了自主开发，还从外部引进。2023年3月，吉利德行使选择权，获得NX-0479（GS-6791）的独家许可。NX-0479是一种有效、选择性口服IRAK4降解剂，靶向IRAK4蛋白激酶的支架和激酶功能，以阻断toll样受体(TLR)和促炎IL1细胞因子受体家族(IL1Rs)下游的炎症反应。与激酶抑制剂相比，GS-6791对IRAK4的降解对TLR/IL1Rs信号的抑制更持久、更深。上述IRAK4靶向药被开发用于治疗自身免疫性疾病，但IRAK4靶向药还有望用于治疗肿瘤，如Curis公司的Emavusertib（CA-4948）被开发用于治疗急性髓细胞性白血病（AML）和骨髓增生异常综合征（MDS）。总结整体来看，IRAK4靶点治疗自身免疫性疾病的潜力已得到初步临床试验验证，不过未来还有很长的路要走。国内外药企积极开发IRAK4靶向药，且研发方向已开始出现新方向，不再局限于小分子化药，已开始研发IRAK4靶向PROTAC降解剂。期待在药企的不懈努力下，IRAK4靶点可以早日突破重围。 END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

蛋白降解靶向嵌合体临床1期临床结果临床2期

2024-08-12

·生物谷

上海中医药大学季光/国海东团队揭示负载miR-146a的牛奶外泌体靶向治疗心肌缺血再灌注损伤的作用及机制

近日，上海中医药大学季光教授和国海东研究员团队在Journal of Nanobiotechnology上发表研究论文Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury。该研究探讨了负载miR-146a的牛奶外泌体对心肌缺血再灌注损伤（MIRI）的治疗作用，并证实负载miR-146a的牛奶外泌体经靶向肽修饰后具有更好的疗效。这一发现为临床治疗MIRI提供新的策略和方法。再灌注治疗对于在心肌梗死后挽救心肌是至关重要的，但是恢复血流的过程本身会加剧对心肌的损伤。这种现象被称为MIRI。已知微小RNA-146a（miR-146a）对心肌损伤后心脏功能改善具有潜在影响。然而，以特定和有效的方式将miR-146a递送至心脏仍然是一个挑战。牛奶外泌体（MEs）有可能是miRNA治疗的理想递送平台。在这项研究中，研究人员以MEs为载体，通过电穿孔将miR-146成功装载至MEs中（MEs-miR-146a），经灌胃给予MIRI大鼠治疗后，发现其可以减少心肌组织凋亡和炎症因子的表达，并且在改善MIRI后的心功能方面显示出有益的效果。为了提高MEs-miR-146a静脉注射后对心肌损伤部位的靶向性，研究人员研发了由缺血心肌靶向肽（IMTP）修饰的功能化MEs系统（IMTP-MEs-miR-146a）。静脉注射IMTP-MEs-miR-146a后，心肌组织中的miR-146a水平显著增加，提示IMTP修饰增强了负载于MEs中的miR-146a向心肌损伤部位的靶向递送，并显示出有效抑制炎症反应，从而在全身给药后发挥更好的治疗作用。因此，IMTP修饰的MEs被证明是用于靶向心脏损伤治疗的miRNA的实用药物递送系统。此外，MEs-miR-146a可以负向调节NF-κB信号通路，降低TRAF6和IRAK1的表达，通过抑制IRAK1/TRAF6/NF-κB信号通路发挥其抗炎作用。综上所述，MEs-miR-146a是一种有前途的治疗MIRI的策略，经IMTP修饰后具有更好的疗效，有望在未来应用于临床实践。上海中医药大学中西医结合学院博士后孟婉婷为论文第一作者，季光教授、国海东研究员和牟芳芳副教授为共同通讯作者。该研究得到国家自然科学基金、上海自然科学基金和上海市学术带头人项目的资助支持。论文链接： Meng WT, Zhu J, Wang YC, et al. Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury. J Nanobiotechnology. 2024;22(1):382. Published 2024 Jul 1. doi:10.1186/s12951-024-02631-0 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床结果专利侵权