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更新于：2025-05-07

TASK-1

更新于：2025-05-07

基本信息

别名

Acid-sensitive potassium channel protein TASK-1、K2p3.1、KCNK3

+ [11]

简介

K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an 'ion flux gating' mode where outward but not inward ion flow opens the gate (PubMed:23169818, PubMed:26919430, PubMed:32499642, PubMed:36195757, PubMed:9312005). Changes ion selectivity and becomes permeable to Na(+) ions in response to extracellular acidification. Protonation of the pH sensor His-98 stabilizes C-type inactivation conformation likely converting the channel from outward K(+)-conducting, to inward Na(+)-conducting to nonconductive state (PubMed:22948150). Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties (PubMed:23169818, PubMed:32499642). Allows K(+) currents with fast-gating kinetics important for the repolarization and hyperpolarization phases of action potentials (By similarity). In cerebellar granule cells, heteromeric KCNK3:KCNK9 channel may hyperpolarize the resting membrane potential to limit intrinsic neuronal excitability, but once the action potential threshold is reached, it may support high-frequency action potential firing and increased neuronal excitability (By similarity). Dispensable for central chemosensory respiration i.e. breathing controlled by brainstem CO2/pH, it rather conducts pH-sensitive currents and controls the firing rate of serotonergic raphe neurons involved in potentiation of the respiratory chemoreflex. Additionally, imparts chemosensitivity to type 1 cells in carotid bodies which respond to a decrease in arterial oxygen pressure or an increase in carbon dioxide pressure or pH to initiate adaptive changes in pulmonary ventilation (By similarity). In adrenal gland, contributes to the maintenance of a hyperpolarized resting membrane potential of aldosterone-producing cells at zona glomerulosa and limits aldosterone release as part of a regulatory mechanism that controls arterial blood pressure and electrolyte homeostasis (By similarity). In brown adipocytes, mediates K(+) efflux that counteracts norepinephrine-induced membrane depolarization, limits Ca(2+) efflux and downstream cAMP and PKA signaling, ultimately attenuating lipid oxidation and adaptive thermogenesis (By similarity).

关联

项与 TASK-1 相关的药物

F3(CEAP)

靶点

TASK-1

作用机制

TASK-1抑制剂

在研机构

Philip Morris International, Inc.

原研机构

Centro de Estudios en Alimentos Procesados

在研适应症

咳嗽

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ML365

靶点

TASK-1

作用机制

TASK-1抑制剂

在研机构

Johns Hopkins Medicine, Inc. [+2]

原研机构

Johns Hopkins Medicine, Inc. [+1]

在研适应症

术后认知功能障碍 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

(+)-Doxapram

靶点

TASK-1 x TASK-3

作用机制

TASK-1抑制剂 [+2]

在研机构-

原研机构

Galleon Pharmaceuticals, Inc.

在研适应症-

非在研适应症

缺氧

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 TASK-1 相关的临床试验

NCT05527457

/ Completed临床1期IIT

Effects of BAY2586116 on Obstructive Sleep Apnoea (OSA) Severity Informed by Upper Airway Physiology and the Role of Route of Breathing

This investigator-initiated study aims to determine the effects of BAY2586116 (a novel TASK channel blocker nasal spray) on sleep apnoea severity and the potential influence of route of breathing.

开始日期2022-08-31

申办/合作机构

Flinders University

[+1]

NCT04872387

/ Completed临床1期

Randomized, Placebo-controlled, Single-blind, Dose Escalation Study to Investigate the Safety, Tolerability, and Pharmacokinetics After Single and Multiple Nasal Doses of BAY 2586116 in Japanese Healthy Male Participants

BAY2586116 is a new drug in development for the treatment of obstructive sleep apnea. This is a condition that causes breathing to repeatedly stop and start during sleep due to blocked upper airways.
This is a study to learn more how safe BAY2586116 is, how it affects the body, how it moves into, through and out of the body in healthy Japanese male participants.
The participants will be randomly chosen to receive 1 of 3 different doses of BAY2586116 or to receive a placebo. A placebo looks like a treatment but does not have any medicine in it. The participants will receive their study treatment either 1 single time or once a day for 5 days through a nasal spray.
The participants will be in the study for a total of about 12 weeks. They will stay at their study site for either 5 or 9 days, depending on which study treatment they receive. During this time, the doctors will take blood and urine samples and check the participants' health. About 6 to 8 days after the participants receive their last treatment, the researchers will check the participants' health again.
The main aim of this study is to learn more about how safe BAY2586116 is compared to the placebo. To answer this question, the researchers will count the number of participants who have medical problems that may or may not be related to the study treatment. These medical problems are also known as "adverse events" while they are in the study.

开始日期2021-05-11

申办/合作机构

Bayer AG

NCT04713826

/ Completed临床2期

Proof-of-concept, Multi-center, Randomized, Double-blind, Placebo-controlled, Two-way Crossover Study to Investigate the Effect Strength of BAY 2586116 on the Apnea-hypopnea-index After Repetitive Nasal Doses Compared to Placebo in 80 Valid Participants With Moderate to Severe Obstructive Sleep Apnea

Researchers are looking for a better way to treat people with obstructive sleep apnea (OSA). In people with OSA, the upper airways can narrow or close repetitively while sleeping. These breathing interruptions lead to reduction of oxygen in the blood or short arousals from sleep. Before a treatment can be approved for people to take, researchers do clinical trials to better understand its safety and how well it works.
In this trial, the researchers want to learn more about how well BAY2586116 works in a small number of participants with OSA. The trial will include about 160 men and women who have OSA and are at least 18 years old. Women can only be included in this trial if they are not able to have children naturally.
In this trial, the participants will take BAY2586116 and a placebo. A placebo looks like a treatment but does not have any medicine in it. All of the participants will take BAY2586116 through a nasal spray. They will also take the placebo as a nasal spray.
This will be a crossover trial. This means all the participants will take both trial treatments one after the other, but in a different order. The participants will take each treatment once a day for 7 days.
The researchers will use a measurement called the apnea-hypopnea-index (AHI) to measure the severity of the participants' OSA. The researchers will then compare the participants' AHI scores when they take BAY2586116 and when they take the placebo.
During study, the participants will visit their trial site 5 times. At these visits the doctors will take blood samples, do physical examinations and check the participants' heart health using an electrocardiogram (ECG). They will also ask the participants questions about how they are feeling and if they have any medical problems. At 3 of the visits, the participants will stay at the trial site overnight. At these visits, the doctors will calculate the number of times the participants stop breathing per hour of sleep. After treatment, the participants will have a final visit 7 days later so the doctors can check their health.

开始日期2021-03-03

申办/合作机构

Bayer AG

100 项与 TASK-1 相关的临床结果

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100 项与 TASK-1 相关的转化医学

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0 项与 TASK-1 相关的专利（医药）

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671

项与 TASK-1 相关的文献（医药）

2025-04-01·Journal of Biological Chemistry

Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

Article

作者: Gutiérrez, Margarita ; Schütte, Sven ; Mazola, Yuliet ; González, Wendy ; Venturini, Whitney ; Rodriguez, Blanca ; Wiedmann, Felix ; Prent-Peñaloza, Luis ; Bedoya, Mauricio ; Márquez Montesinos, José C E ; Bueno-Orovio, Alfonso ; Prüser, Merten ; Dasí, Albert ; Decher, Niels ; Zúñiga, Rafael ; Kiper, Aytug K ; Varela, Diego ; Adasme-Carreño, Francisco ; Camargo-Ayala, Lorena ; Peña-Martínez, Paula A ; Camargo-Ayala, Paola Andrea ; Rinné, Susanne ; Zúñiga, Leandro ; Schmidt, Constanze ; Ravens, Ursula

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na_V1.5, K_V1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC₅₀ ∼ 0.3 μM), a moderate inhibition of Na_V1.5 (IC₅₀ ∼ 21.2 μM) and a subtle inhibition of K_V1.5 (IC₅₀ ∼ 81.5 μM), alongside unexpected activation of TASK-4 (∼ 40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and patients with AF revealed that 6f reduced action potential amplitude in SR (indicating Na_V1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.

2025-03-05·ACS Chemical Neuroscience

Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator In Vivo Tool Compound

Article

作者: Mori, Takahiro ; Sekioka, Yoko ; Lindsley, Craig W. ; Denton, Jerod S. ; Boutaud, Olivier ; Kurata, Haruto ; Yashiro, Kentaro ; Engers, Darren W. ; Isami, Koichi ; McGowan, Kevin M. ; Kokubo, Masaya ; Bridges, Thomas M. ; Kato, Junya ; Iwaki, Yuzo ; Wieting, Joshua ; Urata, Hirohito

Herein we describe our initial work on the K₂P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = 19b) emerged as a reasonably potent (human Tl⁺; TREK-1 EC₅₀ = 2.8 μM (95% E_max), TREK-2 EC₅₀ = 0.30 μM (184% E_max)), first-generation CNS penetrant (rat K_p = 0.37) in vivo tool compound with selectivity versus the other K₂P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of in vivo tool compounds for the community.

2025-01-22·Current Pharmaceutical Biotechnology

Integrative Bioinformatics and Experimental Validation Reveal the Mechanistic Action of Patchouli Alcohol in Prostate Cancer Treatment

Article

作者: Zhao, Juan ; Cai, Jian ; Zhai, Songhui

Introduction:Prostate cancer is an androgen-dependent malignancy, and the use of androgen deprivation therapies frequently results in treatment resistance, relapse, and the development of aggressive castration-resistant tumors. Patchouli alcohol, a tricyclic sesquiterpene derived from Pogostemon cablin of the Labiatae family, has demonstrated potential in modulating inflammatory responses and tumor progression. This study aimed to investigate the mechanisms through which patchouli alcohol influences inflammatory pathways associated with prostate cancer using bioinformatics and experimental validation.Methods:Differentially Expressed Genes (DEGs) were identified from the GSE46602 dataset, containing 36 prostate cancer and 14 normal prostate biopsy samples, using the GEO2R tool (adjusted P < 0.05). Functional annotation was performed using GO and KEGG databases, while PPI networks were constructed via STRING and Cytoscape. Key hub genes were identified. To validate the bioinformatics findings, qPCR and Western blotting were employed to confirm the differential expression of selected hub genes in DU145 prostate cancer cells treated with patchouli oil.Results:Bioinformatic analysis revealed 71 DEGs, including 35 upregulated and 36 downregulated genes. Thirteen hub genes were identified (DCK, APRT, ADK, KCNK9, ADSL, PKM, KCNK3, S100A10, ENTPD2, PKLR, ARHGEF38, TPK1, and AK5), which were enriched in pathways, such as MAPK, PI3K-Akt, Ras, and Rap1. Experimental validation confirmed the upregulation of DCK, APRT, KCNK9, ADSL, PKM, S100A10, ENTPD2, PKLR, ARHGEF38, and AK5, and the downregulation of ADK, KCNK3, and TPK1 at both the mRNA and protein levels.Conclusion:Patchouli alcohol appears to influence multiple hub genes associated with prostate cancer progression through its modulation of key cellular signaling and metabolic pathways. These findings support its potential role as a therapeutic agent for prostate cancer.

项与 TASK-1 相关的新闻（医药）

2023-02-16

·BioSpace

GeneDx Rare Disease Data Demonstrates Utility in Drug Candidate Identification for Common Diseases Research published in Nature Genetics underscores the role of genetic insights in the drug discovery and development process

STAMFORD, Conn., Feb. 16, 2023 (GLOBE NEWSWIRE) -- GeneDx Holdings Corp. (GeneDx) (Nasdaq: WGS), a leader in delivering improved health outcomes through genomic and clinical insights, continues to demonstrate how the study of rare disease can improve understanding of the biology of common disorders. Research published in the October 2022 issue of Nature Genetics, to which GeneDx contributed data and authorship, yields insights into the role of two-pore-domain potassium channels (K2P) in rare disease and explores the role genes might play in the newly described developmental delay with sleep apnea (DDSA). Such connections better enable the exploration of pharmacological solutions to common diseases impacting wide swaths of the general population. Sleep apnea, characterized by abnormal, interrupted breathing during sleep, is a common disorder that represents a global public health burden thought to affect up to one in five people worldwide and approximately 30 million Americans. Poor sleep quality often results in decreased quality of life and increased risk of comorbidities, such as cardiovascular disease, diabetes and depression. The study describes DDSA, a newly identified condition caused by de novo gain-of function variants clustering in the X-gate motif of the TASK-1 channel encoded by KCNK3. TASK-1 is a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Functional studies indicate that TASK channel inhibitors may be effective at inhibiting abnormal channel activity caused by these variants, illuminating the underlying biology of sleep apnea and pointing to possible therapeutic options for patients with DDSA and common sleep apnea. “These findings indicate how research into rare disease can uncover findings that are potentially applicable to much broader segments of the general population and also represent important progress for the pharmacological management of sleep apnea,” said Dr. Paul Kruszka, Chief Medical Officer of GeneDx. “Sleep apnea’s high prevalence and the imperfection of existing therapies mean there is sizeable appetite for developing new treatment approaches.” Through its robust rare disease data set, GeneDx is working to advance drug discovery and development, and accelerate research to help identify therapeutic targets for common diseases. With the deep genomic information available from GeneDx’s exome and genome testing, combined with its clinical insights, the company is able to help connect biopharmaceutical companies with patients to improve clinical trial enrollments and recruitment and improve patient outcomes by connecting them to therapies. About GeneDx (formerly Sema4) GeneDx delivers personalized and actionable health insights to inform diagnosis, direct treatment and improve drug discovery. The company is uniquely positioned to accelerate the use of genomic and large-scale clinical information to enable precision medicine as the standard of care. GeneDx is at the forefront of transforming healthcare through its industry-leading exome and genome testing and interpretation, fueled by one of the world’s largest rare disease data sets. For more information, please visit genedx.com and connect with us on LinkedIn, Facebook, and Instagram. Media contact Stephanie Kahan Press@genedx.com Investor contact Tricia Truehart Investors@genedx.com

2023-01-03

·BioBAY

行业洞见丨2022年度100个新靶点

新靶点发现是药物研发取得创新突破的重要支撑。对于机制不明，缺乏明确靶点的疾病来说，找到正确药靶将大大加速突破性疗法的诞生。一个里程碑靶点的发现亦可催生多款“重磅炸弹”药物。转眼2022年已经过去，这一年全球科学家和药物研发人员在新靶点发现方面依然取得了多项重要成果。下面我们分享由医药魔方Pro梳理并筛选出的2022年值得关注的100个新靶点，希望能够给国内创新药研发人员和投资者提供一些参考。2021年底，医药魔方Pro首次推出了《100个新靶点》年度盘点特别企划文章，受到了读者的广泛关注。转眼2022已接近尾声，这一年，全球科学家和药物研发人员在新靶点发现方面依然取得了多项重要成果。例如，在癌症方面，数十个新靶点涌现，其中不乏MC5R、RASA2、TMEM251、P2X4 receptor、FMRP等里程碑靶点；此外，科学家们发现了多个有望助力CAR-T治疗实体瘤的新靶点，如PTP1B、CDH17、PARP11、PRDM1、NR4A3等。在AD领域，多个潜力靶点“浮出水面”，包括PLD3、MFG-E8、FSH、interferon、HCAR2、ATAD3A。值得一提的是，其中有两个里程碑靶点（PLD3、FSH）由中国科学家参与发现。在新冠方面，2022年也有多个新靶点被发现，包括FXR、DOCK2、caspase-6、NSP6等。其中FXR阻断剂因具有补充COVID-19疫苗预防作用的潜力而引发关注。今年，除了针对不同适应症的全新靶点，还有一些老靶点的新潜在适应症被发现，其中最具代表性的是PD-L1，有两个科学家团队分别发现靶向PD-L1有望治疗肥胖和衰老。除了“老靶点新适应症”，值得一提的是，2月24日发表在Nature杂志上的一项研究中，厦门大学林圣彩院士团队在“明星药物”二甲双胍诞生百年后，终于破解了该药的分子靶点——PEN2。除此之外，过去一年，帕金森病、抑郁症、心血管疾病、非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）、系统性红斑狼疮、银屑病、多发性硬化症、瘙痒、纤维化疾病、哮喘、睡眠呼吸暂停等疾病领域也都在靶点发现方面有新进展。岁末之际，医药魔方Pro梳理并筛选出了2022年值得关注的100个新靶点（详见文末表格），希望能够给国内创新药研发人员和投资者提供一些参考。在这100个新靶点中，有20个入选医药魔方NextPharma转化医学里程碑成果，具体如下：里程碑靶点（1）：FXR杂志：Nature领域：COVID-19论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-05594-0成果：12月5日，Nature杂志发表了英国剑桥大学Fotios Sampaziotis等人的最新研究成果，介绍了一种补充COVID-19疫苗接种的新型化学预防方法。研究确定了法尼醇X受体（FXR）控制血管紧张素转换酶2（ACE2）表达的新功能，并提供了调节该通路有助于减少SARS-CoV-2感染的证据。ACE2位于人体细胞膜，是SARS-CoV-2进入和感染细胞的主要通道。通过类器官实验，研究人员发现阻断一种叫做FXR的胆汁酸敏感蛋白可以减少ACE2在细胞表面的数量。FXR广泛存在于肝脏细胞表面，在身体其他部位也有分布。熊去氧胆酸（UDCA）是一种阻断FXR并可治疗某些肝脏疾病的药物。以UDCA处理人类肺、肠和肝脏类器官模型，ACE2水平显著降低，SARS-CoV-2细胞感染水平下降。为确证这一发现，实验人员以UDCA处理仓鼠，结果表明这类药物可以预防SARS-CoV-2感染。进一步的验证实验中，研究人员在一对不适宜移植的捐赠人肺中测试UDCA。以SARS-CoV-2处理肺脏前，研究人员对肺脏进行通气并用血液样液体灌注以维持其活性。随后，以UDCA的生理盐水溶液处理其中一个肺脏，另一个肺脏仅以生理盐水处理作为对照。数据显示，UDCA处理的肺脏中SARS-CoV-2的感染水平下降。8例接受UDCA治疗的健康受试者中，病毒进入细胞主要入口的鼻细胞中ACE2水平降低，理论上可以提高人体对SARS-CoV-2的抵抗力。里程碑靶点（2）：PLD3杂志：Nature领域：阿尔茨海默病论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-05491-6成果：11月30日，复旦大学青年研究员袁鹏与美国耶鲁大学Grutzendler团队合作，于Nature在线发文报道，他们发现阿尔茨海默病（AD）中β-淀粉样蛋白（Aβ）沉积周围存在大量的轴突球状体的膨大病变结构，它们阻碍神经信号传导，影响神经网络功能，而溶酶体蛋白PLD3可以作为调控此病变的分子靶点，能逆转球体状病变和神经传导异常，指出了AD治疗中一类不依赖淀粉样蛋白清除的潜在新策略。里程碑靶点（3）：FMRP杂志：Science领域：癌症、免疫疗法论文：DOI：10.1126/science.abl7207成果：11月18日，发表在Science杂志上的一项研究中，来自瑞士洛桑联邦理工学院（EPFL）等机构的研究人员发现，一种名为脆性X染色体智力迟滞蛋白（FMRP）的蛋白质在帮助肿瘤逃避免疫系统攻击方面起着关键作用。通常，FMRP参与调节神经元中的蛋白质翻译和mRNA的稳定性，但这项研究证明它在多种癌症中表达上调。研究还显示，表达FMRP的肿瘤会产生IL-33，这是一种诱导调节性T细胞（Treg）产生的蛋白质，而Treg可以抑制免疫反应。它们还产生蛋白质S，一种已知可促进肿瘤生长的糖蛋白。最后，肿瘤产生外泌体，触发一种通常有助于伤口愈合和组织修复的巨噬细胞（M2型）的产生。这3个因素都具有免疫抑制性，有助于肿瘤抵抗T淋巴细胞攻击。相反，FMRP敲除肿瘤细胞实际上下调了所有3种因子（IL-33、蛋白S和外泌体），同时上调了一种不同的趋化因子CCL7，这有助于招募和激活T细胞。这一过程通过诱导免疫刺激巨噬细胞（M1型）而得到进一步的帮助。这些细胞产生其他3种促炎蛋白，它们与CCL7一起招募T细胞。总结来看，这项工作发现了一种先前未被认识到的肿瘤逃避免疫攻击的机制，证明FMRP是一种新的有潜力的癌症治疗靶点，值得进一步开发。EPFL已经基于这项成果孵化了Opna Bio。里程碑靶点（4）：P2X4 receptor杂志：Nature领域：癌症（结直肠癌）论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-05426-1成果：11月16日，发表在Nature杂志上的一项研究中，来自德国的一个科学家团队揭示，在患者来源的结直肠肿瘤类器官中，化疗诱导的肿瘤细胞死亡导致ATP释放，触发P2X4（也称为P2RX4）以调节邻近癌细胞中mTOR依赖性促生存程序，进而使得存活肿瘤上皮细胞对mTOR抑制敏感。抑制P2X4受体（P2X4 receptor）或直接mTOR阻断可与化疗协同，导致大量细胞死亡及显著的肿瘤消退。这些发现为表达P2X4的上皮肿瘤的联合治疗创造了机会。里程碑靶点（5）：MFG-E8杂志：Nature领域：阿尔茨海默病论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-05440-3成果：科学家们在50岁以上的几乎所有人的脉管系统中都发现了medin淀粉样蛋白（MFG-E8蛋白的片段）的聚集物，使其成为目前已知的最常见的淀粉样蛋白。11月16日，发表在Nature杂志上的一项研究中，来自德国神经退行性疾病中心的一个科学家团队揭示，在淀粉样蛋白-β前体蛋白（APP）转基因小鼠及阿尔茨海默病患者中，medin与血管淀粉样蛋白-β沉积物共定位；在小鼠模型中，medin缺乏使血管淀粉样蛋白-β沉积减少了一半。此外，在小鼠和人脑中，MFG-E8在血管系统中高度富集，MFG-E8和medin水平随着血管淀粉样蛋白-β负担的严重程度而升高。此外，通过分析来自ROSMAP队列中566名个体的数据，研究发现阿尔茨海默病患者具有较高的MFG-E8表达水平，且这种高表达与认知能力下降的增加有关。在机制上，科学家们证明了medin直接与淀粉样蛋白-β相互作用促进其聚集，因为medin与淀粉样蛋白-β形成异源原纤维，影响淀粉样蛋白-β原纤维结构，并在体外和体内cross-seed淀粉样蛋白-β聚集。因此，medin可能是预防大脑血管中淀粉样蛋白-β沉积引起的血管损伤和认知能力下降的治疗靶点。里程碑靶点（6）：SERT-nNOS杂志：Science领域：抑郁症论文：DOI：10.1126/science.abo3566成果：10月28日，Science发表了南京医科大学生殖医学国家重点实验室、药学院周其冈教授、朱东亚教授、厉廷有教授联合团队的突破成果：该团队的研究发现了一个全新的快速起效的抗抑郁靶点——SERT（5-羟色胺转运子）-nNOS（神经元型一氧化氮合酶），其解偶联剂能够快速起效，并且有可能克服第三代抗抑郁药物依赖于5-羟色胺自身受体脱敏的缺陷，发展全新一代抗抑郁药物。Science将该研究列为Highlight，同行评价这是抗抑郁药物研究取得的重大理论突破。里程碑靶点（7）：TASK-1杂志：Nature Genetics领域：睡眠呼吸暂停论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41588-022-01185-x成果：睡眠呼吸暂停是一种常见的疾病。KCNK3编码的TASK-1是一个与呼吸控制有关的K通道，但它与睡眠呼吸暂停的联系知之甚少。10月4日，来自英国牛津大学等机构的科学家们在一篇Nature Genetics论文中描述了一种由KCNK3罕见的新生功能获得性突变引起的伴有睡眠呼吸暂停的新发育障碍（developmental delay with sleep apnea，DDSA）。突变聚集在“X-gate”周围，产生过度活跃的通道，不再响应GPCR通路的抑制。不过，尽管有缺陷的X-gating，这些突变通道仍然可以被一系列已知的TASK通道抑制剂抑制。这些结果不仅突出了TASK-1 K通道的重要新作用及其与睡眠呼吸暂停的联系，而且还确定了可能的治疗策略。里程碑靶点（8）：TMEM251杂志：Science领域：癌症论文：DOI：10.1126/science.abn5637成果：哺乳动物细胞可以通过巨胞饮和细胞外蛋白质的溶酶体分解产生氨基酸，癌细胞利用这些氨基酸在营养不良的肿瘤中生长。9月8日，发表在Science杂志上的一项研究中，来自德国及奥地利的科学家团队通过在指定营养条件下的遗传筛选鉴定出了LYSET，一种细胞消耗细胞外蛋白时选择性需要的跨膜蛋白（TMEM251）。LYSET在高尔基体中被发现与GlcNAc-1-磷酸转移酶相关，该酶通过甘露糖-6-磷酸修饰将分解代谢酶靶向为溶酶体。缺乏LYSET时，GlcNAc-1-磷酸转移酶不稳定。LYSET缺陷细胞巨胞饮和自噬“货物”周转受损。因此，科学家们认为，LYSET（TMEM251）是溶酶体酶运输途径的核心组成部分，并可能是抑制癌症代谢适应的靶点。里程碑靶点（9）：GnRH杂志：Science领域：唐氏综合征论文：DOI：10.1126/science.abq4515成果：目前，还没有可行的治疗唐氏综合征（DS）的认知和嗅觉缺陷的方法。9月2日，来自瑞士和法国的科学家团队在Science杂志发表的一项成果显示，在DS模型（Ts65Dn小鼠）中，这些进行性非生殖神经症状与促性腺激素释放激素（GnRH）表达异常密切相关。恢复生理GnRH水平的表观遗传、细胞、化学遗传学和药理学干预可消除Ts65Dn小鼠的嗅觉和认知缺陷，而脉冲GnRH疗法可以改善成人DS患者的认知能力和大脑连通性。因此，GnRH在嗅觉和认知中起着至关重要的作用，脉冲GnRH疗法有望改善DS的认知缺陷。里程碑靶点（10）：RASA2杂志：Nature领域：癌症、免疫疗法、CAR-T、TCR-T论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-05126-w成果：8月24日，发表于Nature杂志上的一篇论文中，来自加州大学旧金山分校等机构的研究人员基于CRISPR技术确定了一种预防T细胞功能障碍的靶点基因——RASA2，并证明敲除该基因可使T细胞更具“韧性”。研究显示，RASA2的消除增强了T细胞对抗原的敏感性，并改善了CAR-T和TCR-T细胞的效应器功能和持久性。此外，抗原特异性T细胞中的RASA2消除可以增强肿瘤控制，并延长血液瘤和实体瘤的多个临床前模型动物的存活时间。里程碑靶点（11）：GPNMB杂志：Science领域：帕金森病论文：DOI：10.1126/science.abk063成果：全基因组关联研究（GWASs）已经确定了帕金森病（PD）的许多风险位点，但靶基因和机制仍然很大程度上未知。8月19日发表在Science杂志上的一篇论文中，来自宾夕法尼亚大学的研究团队将GWAS衍生的7号染色体位点（前哨单核苷酸多态性rs199347）与GPNMB联系起来。在细胞中，糖蛋白非转移性黑色素瘤蛋白B（GPNMB）与α-突触核蛋白（aSyn）共免疫沉淀并共定位。在诱导多能干细胞来源的神经元中，GPNMB的缺失导致aSyn原纤维内化以及发展成aSyn病理的能力的丧失。在731例PD和59例对照生物样本中，GPNMB在PD血浆中升高，与疾病严重程度相关。因此，科学家们认为，GPNMB代表了PD风险基因，具有生物标志物开发和治疗靶向的潜力。里程碑靶点（12）：MC5R杂志：Science领域：癌症、免疫疗法论文：DOI：10.1126/science.abj2674成果：8月4日，中国科学技术大学生命科学与医学部周荣斌、江维教授团队与转化医学与创新药物国家重点实验室唐任宏团队合作，在Science发表研究论文，报道了下丘脑-垂体轴及其产生的激素α-促黑细胞刺激素（α-MSH）在介导肿瘤诱导的髓系造血和免疫抑制中的关键作用。研究显示，不管是免疫检查点治疗（ICT）敏感还是抵抗的肿瘤模型中，利用多肽抑制剂阻断α-MSH的受体MC5R均可抑制肿瘤生长，且MC5R多肽抑制剂与抗PD-1抗体联合使用可提高ICT的效率。此外，研究发现非小细胞肺癌和恶性头颈癌患者血清中α-MSH浓度显著升高并与外周血中的骨髓来源的抑制性细胞（MDSCs）比例呈正相关。这些结果表明，MC5R可以作为一个潜在的肿瘤免疫治疗新靶点。里程碑靶点（13）：ASGR1杂志：Nature领域：高胆固醇血症论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-05006-3成果：高浓度胆固醇引发的心血管疾病越来越多，降脂是预防和治疗心血管疾病的必要手段。8月3日，中国科学院院士、武汉大学生命科学学院、泰康生命医学中心教授宋保亮实验室在Nature发表论文，揭示抑制ASGR1蛋白促使胆固醇外排入胆汁，进一步通过粪便排出机体，从而降低血液和肝脏脂质水平，对动脉粥样硬化和脂肪肝有明显疗效。研究人员研发了ASGR1的中和抗体，该抗体可以有效促使胆固醇外排，并和他汀及依折麦布有良好的协同降脂效果。很多疾病如心血管疾病、脂肪肝和神经退行性疾病等的发生，都与胆固醇的堆积密切相关。这项研究工作为研发促使胆固醇外排的降脂药物奠定了重要基础。里程碑靶点（14）：CIDEB杂志：NEJM领域：非酒精性脂肪性肝炎、非酒精性脂肪性肝病论文：DOI：10.1056/NEJMoa2117872成果：7月28日，Regeneron Genetics Center LLC（RGC）的科学家们在发表于NEJM上的一篇论文中称，他们发现了CIDEB基因中罕见的基因功能缺失突变，其与包括非酒精性脂肪性肝炎（NASH）和肝硬化等严重肝脏疾病的实质性保护有关。RGC对5个祖先群体和多个队列（包括UK Biobank和 Geisinger Health System MyCode队列）中超过54万人的外显子进行了测序。通过分析这些遗传数据，研究人员发现，CIDEB基因两个拷贝中的一个携带功能缺失突变的个体，其非酒精性肝病的风险降低约53%，非酒精性肝硬化的风险降低约54%。因此，通过阻断CIDEB表达或功能，有效模拟这些保护性突变的疗法可能有助于预防或治疗NASH和其他形式的肝病。里程碑靶点（15）：INHBE杂志：Nature Communications领域：肥胖论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-022-31757-8成果：7月27日，Alnylam与合作机构在Nature Communications杂志上发表的一篇论文分析了来自英国生物库超过360 000份样本测序数据后发现，肝细胞因子中罕见的INHBE突变与BMI调整的腰臀比（WHRadjBMI，与2型糖尿病和冠心病有因果关系的腹部脂肪的替代指标）减少有关，这表明INHBE是一种潜在的治疗靶点。里程碑靶点（16）：FLCN杂志：Science领域：非酒精性脂肪性肝炎、非酒精性脂肪性肝病论文：DOI：10.1126/science.abf8271成果：非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）仍然没有有效的治疗方法。4月15日，发表在Science杂志上的一篇论文中，来自宾夕法尼亚大学等机构的科学家们发现，在小鼠中通过删除RagC/D鸟苷三磷酸酶激活蛋白folliculin（FLCN）选择性抑制mTORC1信号，能够促进肝脏中转录因子E3 （TFE3）的激活（不影响其他mTORC1靶点），使小鼠免受NAFLD和NASH的危害。疾病保护由TFE3介导，它既能诱导脂肪消耗，也能抑制合成代谢脂肪的生成。科学家们认为，这些数据表明，选择性抑制mTORC1是治疗NASH和NAFLD的潜在方法。里程碑靶点（17）：FSH杂志：Nature领域：阿尔茨海默病论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-04463-0成果：阿尔茨海默病在老年女性中发病率更高，认知能力下降会急剧上升，这与绝经过渡期内脏脂肪过多、能量稳态失调和骨质流失有关。先前的研究显示，抑制卵泡刺激素（FSH）的作用可以减少小鼠体内脂肪，促进产热，增加骨量并降低血清胆固醇。3月2日，发表在Nature杂志上的一项研究中，来自中国科学院深圳理工大学的叶克强教授及其合作者则发现FSH直接作用于海马和皮质神经元，加速淀粉样蛋白β和Tau沉积，并损害显示阿尔茨海默病特征的小鼠的认知能力。通过抑制神经元C/EBPβ-δ-分泌酶途径，在这些小鼠中阻断FSH的作用可以消除阿尔茨海默病样表型。这些数据不仅表明了血清FSH水平升高在绝经期阿尔茨海默病病理生理学中的因果作用，而且还揭示了使用单一FSH阻断剂治疗阿尔茨海默病、肥胖、骨质疏松和血脂异常的机会。里程碑靶点（18）：PEN2杂志：Nature领域：2型糖尿病论文：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-04431-8成果：二甲双胍诞生于上个世纪20年代的欧洲，是一种近百年的老药。自问世以来，它便以临床上的优异表现跻身为糖尿病治疗领域的王牌药物。它在有效降低糖尿病人血糖的同时，并不会引起低血糖、酸中毒等副作用，同时还可以缓解脂肪肝，提高胰岛素敏感性，改善心血管功能。此外，二甲双胍还有抗衰老、延长寿命、抗癌的效用，进而被冠上了“神药”的称号。然而，尽管有着如此耀眼的作用，其分子靶点却一直没有弄清，这极大地限制了人们对二甲双胍的理解和应用。厦门大学林圣彩院士团队长期致力于细胞信号转导的研究。从2014年起他们就对二甲双胍产生了兴趣。经过探索，该团队在2016年于Cell Metabolism上报道了二甲双胍通过溶酶体通路激活蛋白质激酶AMPK的初步结论。AMPK蛋白质激酶是细胞中调节多种代谢途径、维持能量平衡的重要分子。二甲双胍的诸多药效正是通过激活AMPK才得以实现。在此基础上，又经过了几年探索，林圣彩院士团队最终找到了二甲双胍的分子靶点——PEN2，并理清了其导向溶酶体通路，激活AMPK的具体方式。相关研究成果于2月24日发表在Nature杂志上。里程碑靶点（19）：BAG5杂志：Science Translational Medicine领域：扩张型心肌病论文：DOI：10.1126/scitranslmed.abf3274成果：大多数遗传性扩张型心肌病（DCM）的病例没有确定的遗传原因。1月19日，发表在Science Translational Medicine杂志上的一项研究中，来自日本的一个科学家团队在5名遗传性DCM患者中发现了编码BAG联合伴侣5蛋白的BAG5基因的纯合截断突变。在3例心动过速诱发心肌病患者中也发现了杂合截断突变。通过基因治疗纠正Bag5突变可以改善DCM表型。这些发现表明，BAG5突变可以导致DCM，如果通过基因检测及早诊断，可能可以通过基因治疗。里程碑靶点（20）：oncostatin M杂志：Science Translational Medicine领域：哮喘论文：DOI：10.1126/scitranslmed.abf8188成果：1月12日，在Science Translational Medicine发表的一篇论文中，来自Genentech的研究团队发现oncostatin M（OSM）是严重哮喘的主要驱动因素，使用OSM特异性阻断抗体能减轻炎症和粘液的产生，而且不会影响体内关键的抗菌途径和抗菌免疫。研究支持治疗重度哮喘的OSM抗体或其它靶向药物的进一步开发。附：2022年值得关注的100个新靶点推荐阅读行业洞见丨ATLATL落户BioBAY，“优等生”的叠加释放了什么产业周期性信号？行业洞见丨生物医药产业最新调查：创新活力犹在，只待春来！行业洞见丨停管线、裁员和卖厂，这是悲观的时刻吗？

细胞疗法免疫疗法疫苗突破性疗法临床研究