更新于：2024-09-19

TMEM175

更新于：2024-09-19

基本信息

别名

Endosomal/lysosomal potassium channel TMEM175、hTMEM175、MGC4618

+ [2]

简介

Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH (PubMed:35750034, PubMed:35333573). Activated at low pH (under pH 4.6) by luminal side protons: selectively mediates lysosomal proton release from lysosomes, eliciting a proton leak that balances V-ATPase activity to maintain pH homeostasis (PubMed:35750034). Regulation of lumenal pH stability is required for autophagosome-lysosome fusion (PubMed:26317472, PubMed:32267231). May also act as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes (PubMed:26317472, PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). The potassium channel activity is however unclear as it was tested in non-physiological conditions for a lysosomal channel (PubMed:35750034). Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors (PubMed:33505021). The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3), a major target of growth factor receptors: in the complex, TMEM175 channel is opened by conformational changes by AKT, leading to its activation (PubMed:33505021). The lysoK(GF) complex is required to protect neurons against stress-induced damage (PubMed:33505021).

关联

项与 TMEM175 相关的药物

BAB-301

靶点

TMEM175

作用机制

TMEM175调节剂

在研机构

Baobab AiBIO Co., Ltd.初创企业

原研机构

Baobab AiBIO Co., Ltd.初创企业

在研适应症

帕金森病

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

AP-6

靶点

TMEM175

作用机制

TMEM175 inhibitors

在研机构

Memorial Sloan Kettering Cancer Center

原研机构

Memorial Sloan Kettering Cancer Center

在研适应症

帕金森病

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

2-PPA

靶点

TMEM175

作用机制

TMEM175 inhibitors

在研机构

Memorial Sloan Kettering Cancer Center

原研机构

Memorial Sloan Kettering Cancer Center

在研适应症

帕金森病

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

100 项与 TMEM175 相关的临床结果

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100 项与 TMEM175 相关的转化医学

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0 项与 TMEM175 相关的专利（医药）

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项与 TMEM175 相关的文献（医药）

2024-09-01·Ageing Research Reviews

Mechanism and therapeutic targets of the involvement of a novel lysosomal proton channel TMEM175 in Parkinson's disease

Review

作者: Zhang, Zhan ; Zheng, Hongcheng ; Yang, Xinling ; Fan, Peidong ; Feng, Tingting

Parkinson's disease (PD), recognized as the second most prevalent neurodegenerative disease in the aging population, presents a significant challenge due to the current lack of effective treatment methods to mitigate its progression. Many pathogenesis of PD are related to lysosomal dysfunction. Moreover, extensive genetic studies have shown a significant correlation between the lysosomal membrane protein TMEM175 and the risk of developing PD. Building on this discovery, TMEM175 has been identified as a novel potassium ion channel. Intriguingly, further investigations have found that potassium ion channels gradually close and transform into hydrion "excretion" channels in the microenvironment of lysosomes. This finding was further substantiated by studies on TMEM175 knockout mice, which exhibited pronounced motor dysfunction in pole climbing and suspension tests, alongside a notable reduction in dopamine neurons within the substantia nigra compacta. Despite these advancements, the current research landscape is not without its controversies. In light of this, the present review endeavors to methodically examine and consolidate a vast array of recent literature on TMEM175. This comprehensive analysis spans from the foundational research on the structure and function of TMEM175 to expansive population genetics studies and mechanism research utilizing cellular and animal models.A thorough understanding of the structure and function of TMEM175, coupled with insights into the intricate mechanisms underpinning lysosomal dysfunction in PD dopaminergic neurons, is imperative. Such knowledge is crucial for pinpointing precise intervention targets, thereby paving the way for novel therapeutic strategies that could potentially alter the neurodegenerative trajectory of PD.

2024-09-01·Stem Cell Research

Systemic knockout of Tmem175 results in aberrant differentiation but no effect on hematopoietic reconstitution

Article

作者: Su, Jingjing ; Wang, Yue ; Sun, Leimin ; Zhao, Chunzhen ; Liu, Leiming ; Yao, Jiyuan ; Zhang, Lingling

Lysosomes play crucial roles in regulating cell metabolism, and K⁺ channels are critical for controlling various aspects of lysosomal function. Additionally, lysosomal activity is essential for maintaining the quiescence of hematopoietic stem cells (HSCs) under both steady-state and stress conditions. Tmem175 is a lysosomal potassium channel protein. To further investigate the role of K⁺ channels in HSCs, our study employed knockout mice to examine the function of Tmem175. Our research findings demonstrate that the deletion of Tmem175 does not disrupt the functionality of HSCs in both stable and stressed conditions, including irradiation and intraperitoneal 5-FU injections. However, we did observe that the absence of Tmem175 impairs the long-term differentiation capacity of HSCs into myeloid differentiated subpopulation cells（In this paper, it is referred to simply as M cells）in HSC transplantation test, while promoting their differentiation into T cells. This suggests that Tmem175 plays a role in the lineage differentiation of HSCs without being essential for their self-renewal or long-term regenerative capabilities.

2024-08-21·Journal of the American Chemical Society

Discovery of Selective Inhibitors for the Lysosomal Parkinson’s Disease Channel TMEM175

Article

作者: Lee, Jooyeon ; Hite, Richard K. ; Oh, SeCheol ; Kim, Songwon ; Kim, Min ; Choi, Ho Jeong ; Sapuru, Vinay

TMEM175 is a lysosomal potassium and proton channel that is associated with the development of Parkinson's disease. Advances in understanding the physiological roles of TMEM175 have been hampered by the absence of selective inhibitors, and studies involving genetic perturbations have yielded conflicting results. Here, we report the discovery and characterization of the first reported TMEM175-selective inhibitors, 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound by 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes. These inhibitors may serve as valuable tools to study the roles of TMEM175 in regulating lysosomal function and provide useful templates for future therapeutic development in Parkinson's disease.

项与 TMEM175 相关的新闻（医药）

2023-11-24

·药时代

6.1亿美元！艾伯维、安进投资的神经退行性疾病公司--Caraway，被默沙东收购

2023年11月21日，默沙东（“MSD”）与Caraway Therapeutics（简称“Caraway”）共同宣布，两家公司已达成最终协议。根据协议条款：默沙东将通过子公司收购Caraway，总金额约6.1亿美元，包括未披露的预付款以及或有里程碑付款。 Caraway利用遗传数据和独特的生物学理解，来开发专有的小分子，激活细胞清除和回收过程-加速清除累积的有毒物质和有缺陷的细胞成分。遗传学的新见解强调了溶酶体功能与多器官系统病理之间的联系，包括中枢神经系统(CNS)、心脏、肾脏和肌肉。以这些机制为靶点，Caraway为患有神经退行性疾病和罕见疾病(包括帕金森病(PD)、肌萎缩性侧索硬化症(ALS)和溶酶体沉积病(lsd)的患者提供潜在的疾病修饰化合物。公司正在推进一系列强大的新型小分子疗法，用于治疗神经退行性疾病和罕见疾病，目前均处于临床前的阶段。 TRPML1：TRPML1是通道粘磷脂亚家族的成员，像其他TRP通道一样，TRPML1 具有六个跨膜螺旋 (S1~S6)，以及一个由 S5、S6和 2 个孔螺旋 (PH1和PH2) 组成的孔区域。它是一种释放 Ca2+的阳离子通道，可以介导溶酶体的钙信号传导和稳态，也是转运和自噬相关事件的重要调节因子。 TRPML1的突变能够导致溶酶体贮积病黏液脂病 IV (MLIV) 的发生，会造成认知、语言和运动缺陷和视网膜变性等各种症状的发生，因此TRPML1作为治疗溶酶体贮积症的靶点，在临床上表现出巨大的潜能。由于神经元对溶酶体贮积更为敏感，而且神经元是终末分化的细胞，一旦死亡后无法得到有效的补充，因此大部分溶酶体贮积症都出现神经系统退行性病变的症状，这一现象也将溶酶体与神经退行性疾病紧密联系起来。其可以分为急性神经退行性病和慢性神经退行性病，前者主要有中风、脑损伤；后者主要有亨廷顿病（HD）、帕金森病（PD）、阿尔兹海默病（AD）等。 TMEM175：TMEM175是一种新型的氢离子激活的氢离子通道（LyPAP），介导氢离子快速流出。TMEM175缺乏可导致溶酶体过度酸化，破坏蛋白水解活性，促进体内帕金森致病相关的α-突触核蛋白聚集。2022年6月，Cell杂志在线发表了美国密西根大学徐浩新（Haoxing Xu）团队的相关研究，证实在溶酶体生理条件下，TMEM175作为氢离子激活的氢离子通道介导溶酶体氢离子外流，平衡V-ATP酶介导的氢离子内流，以维持稳定的溶酶体pH值。此外，作为维持溶酶体最佳pH值的氢离子激活的氢离子通道TMEM175在细胞水平上调节溶酶体蛋白水解酶Cathepsin B和Cathepsin D活性，以及体内α-突触核蛋白的清除，为PD、AD等神经退行性疾病和LSDs的病理过程和治疗方法研究提供新思路。 2018年11月，Caraway前身Rheostat Therapeutics宣布完成2300万美元A轮融资，该轮融资由MRLV和AbbVie Ventures领投，包括Amgen Ventures, Alexandria Venture Investments和Mayo Clinic。现有投资者SV Health investors和Dementia Discovery Fund跟投。 2021年6月，该公司曾与艾伯维达成一项合作，开发和商业化靶向TMEM175的小分子疗法，首付款1700万美元。参考资料 1、公司官网 2、公众号：晶蛋生物、医药魔方 3、Hu M, Li P, Wang C, et al. Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes[J]. Cell, 2022, 185(13): 2292-2308. e20. 内容来源于网络，如有侵权，请联系删除。

并购

2023-11-21

·药明康德

获默沙东逾6亿美元青睐，这家新锐如何攻克神经退行性疾病？

▎药明康德内容团队编辑今日，默沙东（MSD）公司宣布，将斥资高达6.1亿美元收购Caraway Therapeutics公司，拓展神经退行性疾病新药研发管线。Caraway Therapeutics公司早在2021年就获得艾伯维（AbbVie）的青睐，与其达成2.67亿美元的帕金森病研发合作协议。这家新锐攻克神经退行性疾病的策略有何不同？Caraway Therapeutics公司聚焦于在多种神经退行性疾病和罕见疾病中出现的有毒细胞成分，它们包括受损的细胞器，蛋白聚集体和聚集的脂质。有效清除这些有毒成分是细胞维持健康必需的功能。而损害清除过程的基因突变与多种神经退行性疾病和罕见病相关。包括阿尔茨海默病，帕金森病，肌萎缩侧索硬化（ALS）等等。Caraway公司的策略是利用遗传学数据和独特的生物学理解，发现激活细胞内降解和再循环机制的小分子化合物，加快毒性产物和失常细胞成分的清除。该公司的研发管线中包括多款针对溶酶体相关靶点的小分子化合物。▲Caraway公司的研发管线（图片来源：Caraway Therapeutics公司官网）其中，TRPML1是主要表达在溶酶体中的钾离子通道，它的正常功能是调控和维持溶酶体的离子组成。激活TRPML1不但增强多种溶酶体蛋白酶的活性，还可以增强葡萄糖脑苷脂酶（glucocerbrosidase，GBA）的表达和活性。而编码GBA的基因发生突变是导致帕金森病发生的最显著遗传风险因子之一。目前，Caraway公司正在开发靶向TRPML1的小分子调节剂，用于治疗GBA相关帕金森病和其它神经退行性疾病。▲TRPML1调节剂治疗GBA相关帕金森病的潜在作用机制（图片来源：Caraway Therapeutics公司官网）编码TMEM175的基因的失活性突变会提高帕金森病发病率，而激活性变异则降低疾病风险。以往体外和动物研究已经证明TMEM175功能受损导致溶酶体pH值不稳定，关键溶酶体蛋白酶的活性下降，以及让细胞更容易被α突触核蛋白损伤。Caraway公司已经发现多款可迅速和可逆性增强TMEM175活性的调节剂，在细胞模型中增强溶酶体的功能。降解神经退行性疾病中的治病蛋白已经成为靶向蛋白降解领域的重要未来研发方向之一。靶向蛋白降解领域明星公司Arvinas的联合创始人之一，耶鲁大学的Craig M. Crews教授和合作伙伴联合曾在Nature Reviews Drug Discovery上发表深度综述，指出靶向蛋白降解的关键性特征之一是能够降解因为没有活性位点而不被传统小分子抑制剂靶向的蛋白。这一特征让在多种神经退行性疾病中积累的蛋白（比如Tau蛋白，α突触核蛋白，亨廷顿蛋白突变体）成为潜在靶点。相关阅读：一切过往，皆为序章！Nature深度综述展望PROTAC四大发展方向虽然目前有PROTAC、LYTAC、分子胶等多种新治疗模式，但是靶向溶酶体靶点的小分子药物在达到降解有毒蛋白目标的同时，可能具有口服利用度高，容易生产等潜在优势。默沙东的新闻稿指出，Caraway公司用小分子调节溶酶体的研发策略提供了攻克神经退行性疾病的新机制，默沙东期待利用其研发能力，为具有未竟需求的患者开发改变疾病进程的疗法。大家都在看▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Merck to Acquire Caraway Therapeutics, Inc. Retrieved November 21, 2023, from https://www.merck.com/news/merck-to-acquire-caraway-therapeutics-inc/[2] Caraway Therapeutics. Retrieved November 21, 2023, from https://carawaytx.com/about/company-overview/[3] Békés et al., (2022). PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery, https://doi.org/10.1038/s41573-021-00371-6免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

蛋白降解靶向嵌合体并购

2023-11-21

·MedCity News

Merck Neuroscience Acquisition Brings a Startup With Parkinson’s, ALS Programs

Merck is shoring up its neuroscience pipeline with the acquisition of Caraway Therapeutics, a preclinical startup with programs in Parkinson’s disease and amyotrophic lateral sclerosis. Specific financial terms were not disclosed, but Merck said Tuesday that the acquisition agreement could pay out up to $610 million, which includes upfront and milestone payments. Cambridge, Massachusetts-based Caraway develops drugs addressing genetically defined neurodegenerative and rare diseases. The company aims to treat them with small molecules that leverage processes in a cell for clearing away toxic cellular components. Mutations can impair the function of lysosomes, cellular components for breaking down and eliminating toxic substances. Caraway’s small molecules modulate lysosomal function. Caraway has two compounds in its program addressing TRPML1, an ion channel located on lysosomes. One of the molecules is in development for Parkinson’s disease stemming from mutations to the GBA gene, which codes for glucocerebrosidase (GCase), an enzyme key to maintaining lipid metabolism. Deficiency of that enzyme leads to lysosomal dysfunction. By activating TRPML1, Caraway aims to address the pathway that is impaired in GBA-Parkinson’s patients. There’s potential competition in treating genetically driven Parkinson’s. Chicago startup Vanqua Bio is developing small molecules that cross the blood-brain barrier to activate GCase and restore lysosomal function. Gene therapies in development by Neurocrine Biosciences and Eli Lilly offer the potential for a one-time fix of Parkinson’s driven by GBA1 mutations. Another TRPML1-targeting small molecule from Caraway is in development for an undisclosed rare disease that is a non-central nervous system disorder. The company is also researching loss-of-function genetic variants of TMEM175, a potassium channel key to lysosomal function. Caraway is developing small molecules that increase TMEM175’s activity to enhance the activity of the lysosome as a potential treatment for Parkinson’s and ALS. “Caraway’s multidisciplinary approach has yielded important progress in evaluating novel mechanisms of modulation of lysosomal function with potential for the treatment of progressive neurodegenerative diseases,” George Addona, senior vice president, discovery, preclinical development and translational medicine, Merck Research Laboratories, said in a prepared statement. “We look forward to applying our expertise to build upon this work with the goal of developing much needed disease-modifying therapies for these conditions.” Caraway was initially called Rheostat Therapeutics. The startup was incubated by SBV Ventures and the Dementia Discovery Fund, which provided seed financing. In 2018, the startup announced a $23 million Series A round co-led by MRLV, the venture investment group of Merck, and AbbVie Ventures. In 2019, Rheostat changed its name to Caraway Therapeutics. Neuroscience is a tiny portion of Merck’s drug portfolio and pipeline, which is dominated by oncology, mainly the cancer immunotherapy Keytruda. But the company has previously looked at TRPML1 as a way to treat neurodegeneration. In 2019, the pharma giant committed up to $576 million to acquire Calporta Therapeutics, a startup that was developing small molecule agonists of TRPLM1. It’s not clear what became of those programs, which are not listed in the company’s pipeline or financial reports. Merck has also turned to partnerships to bolster its neuroscience prospects. Last year, it paid Cerevance $25 million up front to begin a collaboration discovering new targets for potential Alzheimer’s disease drugs. Image: Dr_Microbe, Getty Images

并购免疫疗法基因疗法