更新于：2024-11-01

MALT1

更新于：2024-11-01

基本信息

别名

MALT lymphoma-associated translocation、MALT1、MALT1 paracaspase

+ [7]

简介

Protease that enhances BCL10-induced activation: acts via formation of CBM complexes that channel adaptive and innate immune signaling downstream of CARD domain-containing proteins (CARD9, CARD11 and CARD14) to activate NF-kappa-B and MAP kinase p38 pathways which stimulate expression of genes encoding pro-inflammatory cytokines and chemokines (PubMed:11262391, PubMed:18264101, PubMed:24074955). Mediates BCL10 cleavage: MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion (PubMed:11262391, PubMed:18264101). Involved in the induction of T helper 17 cells (Th17) differentiation (PubMed:11262391, PubMed:18264101). Cleaves RC3H1 and ZC3H12A in response to T-cell receptor (TCR) stimulation which releases their cooperatively repressed targets to promote Th17 cell differentiation (By similarity). Also mediates cleavage of N4BP1 in T-cells following TCR-mediated activation, leading to N4BP1 inactivation (PubMed:31133753). May also have ubiquitin ligase activity: binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity (PubMed:14695475).

关联

项与 MALT1 相关的药物

Safimaltib

靶点

MALT1

作用机制

MALT1抑制剂

在研机构

Janssen Research & Development LLC

原研机构

Janssen Research & Development LLC

在研适应症

难治性B细胞淋巴瘤 [+4]

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

RHX-317

靶点

MALT1

作用机制

MALT1抑制剂

在研机构

Rheos Medicines, Inc.初创企业

原研机构

Rheos Medicines, Inc.初创企业

在研适应症

移植物抗宿主病

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

SGR-1505

靶点

MALT1

作用机制

MALT1抑制剂

在研机构

Schrödinger, Inc.

原研机构

Schrödinger, Inc.

在研适应症

B细胞白血病 [+14]

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 MALT1 相关的临床试验

NCT06622226 / Not yet recruiting临床1期

A Phase 1, Open-label, Dose Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of ONO-7018 in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma (NHL) in Japan

ONO-7018 is a selective inhibitor of mucosa associated lymphoid tissue protein 1 (MALT1) and is expected to exhibit antitumor activity in NHL. This study is Phase1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (biomarkers) and efficacy of ONO-7018 in patients with relapsed or refractory NHL.

开始日期2024-10-01

申办/合作机构

Ono Pharmaceutical Co., Ltd.

CTRI/2024/09/074081 / Not yet recruiting临床1期

A Phase 1, Open Label, Dose Escalation, Multicenter Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Oral AUR104 in Patients with Select Relapsed/Refractory Lymphoid Malignancies (VIJAY-1) - VIJAY-1

开始日期2024-09-30

申办/合作机构

Aurigene Oncology Ltd.

[+1]

ACTRN12623000464662 / Completed临床1期

Part C: A 4-Part Dose-Escalation, Food Effect, And Drug-Drug Interaction Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of SGR-1505 In Healthy Volunteers

开始日期2023-08-25

申办/合作机构

Schrödinger, Inc.

100 项与 MALT1 相关的临床结果

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100 项与 MALT1 相关的转化医学

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0 项与 MALT1 相关的专利（医药）

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1,339

项与 MALT1 相关的文献（医药）

2024-12-01·European Journal of Pharmacology

Sonic hedgehog signaling facilitates pyroptosis in mouse heart following ischemia/reperfusion via enhancing the formation of CARD10-BCL10-MALT1 complex

Article

作者: Li, Ming-Rui ; Lu, Li-Qun ; Zhang, Yi-Yue ; Luo, Xiu-Ju ; Dai, Shu-Yan ; Peng, Jun ; Tang, Can ; Yao, Bi-Feng

Pyroptosis has been found to contribute to myocardial ischemia/reperfusion (I/R) injury, but the exact mechanisms that initiate myocardial pyroptosis are not fully elucidated. Sonic hedgehog (SHH) signaling is activated in heart suffered I/R, and intervention of SHH signaling has been demonstrated to protect heart from I/R injury. Caspase recruitment domain-containing protein 10 (CARD10)-B cell lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex could transduce signals from the membrane and induce inflammatory pathways in non-hematopoietic cells, which could be a downstream effector of SHH signaling pathway. This study aims to explore the role of SHH signaling in I/R-induced myocardial pyroptosis and its relationship with the CBM complex. C57BL/6J mice were subjected to 45 min-ischemia followed by 24 h-reperfusion to establish a myocardial I/R model, and H9c2 cells underwent hypoxia/reoxygenation (H/R) to mimic myocardial I/R model in vitro. Firstly, SHH signaling was significantly activated in heart suffered I/R in an autocrine- or paracrine-dependent manner via its receptor PTCH1, and inhibition of SHH signaling decreased myocardial injury via reducing caspase-11-dependent pyroptosis, concomitant with attenuating CBM complex formation. Secondly, suppression of SHH signaling decreased protein kinase C α (PKCα) level, but inhibition of PKCα attenuated CBM complex formation without impacting the protein levels of SHH and PTCH1. Finally, disruption of the CBM complex prevented MALT1 from recruiting of TRAF6, which was believed to trigger the caspase-11-dependent pyroptosis. Based on these results, we conclude that inhibition of SHH signaling suppresses pyroptosis via attenuating PKCα-mediated CARD10-BCL10-MALT1 complex formation in mouse heart suffered I/R.

2024-11-01·Food Chemistry

Presence of melatonin in foods of daily consumption: The benefit of this hormone for health

Review

作者: Muñoz-Jurado, Ana ; Escribano, Begoña M

Melatonin (MLT) is a hormone that exists in all living organisms, including bacteria, yeast, fungi, animals, and plants, many of which are ingested daily in the diet. However, the exact concentrations of melatonin in each of the foods and the effect on health of the intake of foods rich in MLT are not known. Therefore, the aim of this review was to gather the available information on the melatonin content of different foods and to evaluate the effect that this hormone has on different pathologies. The amount of MLT may vary depending on the variety, origin, heat treatment, processing, and analysis technique, among other factors. Dietary interventions with foods rich in MLT report health benefits, but there is no evidence that hormone is partially responsible for the clinical improvement. Therefore, it is necessary to evaluate the MLT content in more foods, as well as the effect that cooking/processing has on the amount of MLT, to estimate its total intake in a typical diet and better explore its potential impact on the health.

2024-10-23·Journal of Agricultural and Food Chemistry

Rab8a Is a Key Target That Melatonin Prevents Lipid Disorder from Atrazine

Article

作者: Wang, Yu-Xiang ; Ma, Xiang-Yu ; Huang, Ning-Ning ; Yang, Tian-Ning ; Li, Jin-Long ; Jian, Ping-An ; Ren, Yi-Fei ; Li, Xue-Nan

Atrazine (ATZ), a widely used herbicide, disrupts mitochondrial function and lipid metabolism in the liver. Melatonin (MLT), a naturally synthesized hormone, combats mitochondrial dysfunction and alleviates lipid toxicity. However, the mechanisms behind ATZ-induced lipid metabolism toxicity and the protective effects of MLT remain unexplored. Mice were randomly assigned to four groups: control (Con), 5 mg/kg MLT, 170 mg/kg ATZ, and a cotreatment group receiving 170 mg/kg ATZ with 5 mg/kg MLT (ATZ+MLT). Additionally, we analyzed the effects of MLT and Rab8a on mRNA and proteins related to mitochondrial function and lipid metabolism disrupted by ATZ in AML12 cells. In conclusion, ATZ induced mitochondrial stress and disrupted fatty acid metabolism in mouse hepatocytes and AML12 cells. Exogenous MLT restores Rab8a levels, regulating fatty acid utilization in mitochondria and mitochondrial function. Notably, targeting Rab8a does not significantly affect mitochondrial function but prevents ATZ-induced lipid metabolism disorders in hepatocytes.

项与 MALT1 相关的新闻（医药）

2024-10-23

·PRNewswire

HotSpot Therapeutics Presents Preclinical Data from MALT1 CBM Signalosome Glue Program at 36th EORTC-NCI-AACR Symposium

BOSTON, Oct. 23, 2024 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present preclinical data from the Company's mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential in NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR Symposium. MALT1 is a component of the CBM protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies and solid tumors. Leveraging the Company's proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule signalosome glue designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1's protease function. "Our proprietary Smart Allostery™ platform has enabled the development of a MALT1 signalosome glue designed to selectively inhibit MALT1's scaffolding function, a distinct activity profile that enables deep inhibition of the NF-kB pathway," said Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics. "As the NF-kB signaling pathway is a well-characterized oncogenic driver, these preclinical data lend support for HST-1021's potential utility for NF-kB-driven tumors, including as a precision oncology approach for solid tumors mediated by this pathway." The presentation describes preclinical data for HST-1021, HotSpot's MALT1 CBM signalosome glue development candidate: In contrast to MALT1 protease inhibitors, HST-1021 demonstrated robust inhibition of CBM signalosome activity. In an NF-kB-driven nasopharyngeal carcinoma patient-derived xenograft model, HST-1021 demonstrated dose-dependent anti-tumor activity, supporting HST-1021's potential for the treatment of NF-kB-driven solid tumors. About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is a clinical-stage biotechnology company that is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AACR会议

2024-10-10

·药智网

当AI制药成为诺奖的焦点

近日，瑞典皇家科学院宣布，将2024年诺贝尔化学奖授予蛋白质设计先驱David Baker教授与AlphaFold开发者Demis Hassabis、John M.Jumpe。继前几日AI教父John J.Hopfield和Geoffrey E.Hinton获得诺贝尔物理学奖后，AI+制药已成为诺奖的焦点。如果以诺贝尔奖作为人类历年科学发展的缩影，那么对制药业而言，诺贝尔生理学或医学奖提供的是作用机制、诺贝尔化学奖提供的是构建方法、诺贝尔物理学奖提供的是处理效率。技术的不断突破，让AI制药站上风口。百舸争流 AI技术在制药领域的应用已经引起了广泛的关注，有数据显示，截至2023年底，全球共有897家AI制药企业。其中国内AI制药企业就达到了93家，而2020年底时仅为16家。从主要布局来看，大多数AI制药公司还是将重心放在了早期药物开发这一起始阶段上。图1 AI制药公司布局图片来源：参考来源3 从AI制药参与者类型来看，主要分为三大类，IT巨头、AI制药企业和大型药企。三类企业依托各自在研发、生态、算法的优势切入行业。表1 AI制药参与企业分类数据来源：公开资料整理为了降本增效，MNC们对AI充满着无限热情，年初的JPM大会上，谷歌母公司Alphabet旗下的AI生物技术公司Isomorphic Labs宣布与礼来和诺华签署了两笔价值近30亿美元的大额交易；赛诺菲更是在去年宣布了“All in AI”战略；近日礼来也任命Thomas J.Fuchs为公司第一任首席人工智能官，各大跨国制药企业动作不断。经统计，仅2023年MNC在AI+药物研发领域就达成了超30项合作，已披露的总价值约100亿美元，单笔总额最高达27亿美元，其热情可见一斑。而在国内，恒瑞、上海医药等传统企业也早于21年与XtalPi等人工智能企业达成合作。图2 部分药企与人工智能企业合作概况图片来源：参考来源5 对于IT巨头而言，依托自身强大的算法与科技实力，作为“卖铲人”获利也是一条一本万利的道路。根据媒体报道，软银集团宣布计划在2025年前共投资1500亿日元（约9.6亿美元）来增强其人工智能(AI)数据中心的运算能力。而腾讯早已参与其中，其投资的中国AI药物研究公司晶泰科技(QuantumPharm)6月13日在香港上市，成为国产AI制药第一股，并且在不久前结束的腾讯全球数字生态大会上，腾讯健康总裁吴文达在发言中指出，腾讯健康依托于大模型打造的解决方案已经在1300多家企业、医院等机构落地。英伟达的参与更加令人注目，这家全球知名的科技公司，通过旗下的风险投资基金NVentures，积极拓展其在AI制药领域的投资版图。据智药局的数据监测显示，从2023年到2024年6月6日，英伟达共参与投资了10家AI制药公司。此外，其自身研发的生成式AI平台NVIDIA BioNeMo，可用于蛋白质结构预测、蛋白质序列生成、分子优化、生成式化学、对接预测等。据悉，已有100多家生物制药和AI药物研发公司使用其BioNeMo平台，包括安进、安斯泰来制药、Cadence、Iambic、Insilico Medicine、Recursion和Terray Therapeutics，风光无限。对于AI制药初创企业而言，还有很长的路要走。从全球来看，目前海外仅有20余家AI制药企业上市，时间集中在2020年之后。图3 海外已上市AI制药企业图片来源：参考来源6 从公布财报看，2023年美国AI制药公司Schrodinger（薛定谔）年收入2.17亿美元，排名第一，其也是首家实现盈利的AI制药企业：其收入主要由三部分组成：软件收入、药物研发收入和其他收入，全年软件收入占了大头，收入为1.591亿美元，增长17.4%。从研发管线来看，靶向MALT1的SGR-1505和靶向CDC7的SGR-2921均处于临床I期。另外，财报提到，未来薛定谔将会把资源越来越多地放在专利药物发现项目上，这也许意味着薛定谔会在未来锚定“卖铲人”的角色。从国内来看，目前仅有一家上市公司晶泰科技于今年6月13日在香港上市，成为国产AI制药第一股。晶泰科技于2014年成立，在2016年，在辉瑞举办的一场全球晶体结构预测盲测比赛上，刚创立不久的晶泰科技实现了100%准确预测，以此为契机开启了与头部跨国药企的战略合作据招股书数据，在IPO前的融资历程中，晶泰科技共完成了8轮融资，累计金额达7.3亿美元（约合人民币52亿元），在全球AI制药企业中融资额排名第一。目前公司拥有160+授权专利，正在进行超39项药物发现项目，已为全球300多家生物技术与制药公司及研究机构提供服务，其中包括全球前20大生物技术与制药公司（按2022年收入计）中的16家。在国内除了晶泰科技外，目前还有进入到递交招股书环节的英汐智能、B+轮的红云生物和奕拓生物以及C轮的药物牧场、深势科技、甫康药业等企业。 AI制药公司们已经进入到上市竞速赛之中。未来如何？ AI制药红透半边天，但是不可否认的事实是截至目前还没有完全由AI研发的新药物进入市场。从融资的角度来看，2021年行业融资金额达历史高点，超过290亿美元，随后开始大幅下挫。图4 历年AI制药融资情况图片来源：参考来源7 分析原因，主要是由于当前AI制药技术不成熟，技术成果转化有障碍等原因。比如文献显示类药物虚拟筛选库已拥有超过360亿种化合物，对于当下考虑到每个分子估计有10-50个构象异构体，总计超过5000亿个对象。虚拟筛选与实际验证的挑战都是巨大的，遑论常用的AI模型通常针对数万种或更少的化合物进行训练，这引发了人们对其在360亿种化合物的化学空间采样方面的有效性产生疑问。预测的有效性与验证成本限制了AI制药的发展，也是目前为何没有一款上市AI药物的主要原因。此外，另外一方面，则是由于很多公司“挂羊头卖狗肉”。在探究AI制药行业时，波士顿咨询曾提出一个新式的词——“AI原生公司”，指的是那些真正拿AI做实事，而不是借着AI的噱头打广告的公司。在进一步的筛选后，波士顿咨询有了惊人的发现，全世界AI制药企业高达700多家，可真正的“AI原生公司”，竟然只有114家（截至报告时间）。技术的不成熟加上部分入局者的不靠谱，导致AI制药的融资与发展受到阻碍，甚至一些明星公司都受到极大的影响。比如业内的明星公司Exscientia，其市值已经从上市之初的超30亿美元跌到了如今的5.97亿美元（截至2024年10月10日）。并且由于其在管线上的接连失误，以及停止了针对A2A靶点的癌症候选药物EXS-21546的I/II期研究，进一步打击了市场信心。最终只能被英伟达投资的另一家AI制药公司Recursion并购，交易金额仅为6.88亿美元，不足上市之初的30%。领头羊尚且如此，何论那些缺乏资金与技术实力的小型AI制药企业。那么，未来会好吗？答案是一定的。对于AI制药企业而言，其应用框架主要包括三个部分：数据收集和整理、使用分子描述符进行化合物表示、人工智能方法及其应用。 AI训练需要大量的数据验证与反馈，但是每一次的反馈与优化都会对下一次的优化进行拓展与提升。这是一个逐步迭代的过程，随着数据的逐渐沉淀、模型的逐渐优化、算力的逐渐提升，当触发了爱因斯坦称为第八大奇迹的“复利”后，AI赋能制药的效率将会指数级的增长。并且，商业的竞争本质是效率的竞争，新领域“first in class”药物所带来的优势是后来者无法比拟的。更快、更准确的药物发现、构建、验证对药企们来说具有无与伦比的吸引力，大浪淘沙之后，AI制药公司前景无限。最后借用默沙东创始人George W.Merck讲过一句话，“我们应当永远铭记：药品是为人类健康而生产，不是为追求利润而制造的。只要我们坚守这一信念，利润必将随之而来。” 随着科技的进步，制药企业终将拿起AI这把效率之刃，劈开那些侵袭人类的病魔！参考来源： 1.《医药行业估值》 2.Artificial Intelligence for Drug Discovery:Are We There Yet?，https://doi.org/10.1146/annurev-pharmtox-040323-040828 3.《AI制药商业模式分析：以英矽智能、晶泰科技为例》，华创证券 4.《全球AI智能制药公司布局情况现状分析（图）：早期药物开发是主要布局领域》，中研网 5.晶泰科技招股书 6.《中国AI制药企业白皮书》 7.《2024，集体逃离AI制药》，智药局 8.《50亿，AI制药最大并购诞生》，东四十条资本 9.《药物简史》 10.《英伟达、软银入局，AI制药是“王炸”还是概念？》，未来数字城市探索者 11.《AI助力新药研发破局上市公司抢滩黄金赛道》，证券时报网 12.《万字长文：AI制药的前世今生、药物发现、结构预测、从头设计、行业图谱》，BiG生物创新社声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 史蒂文转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

高管变更

2024-10-09

·PRNewswire

HotSpot Therapeutics to Present Preclinical Data from MALT1 CBM Signalosome Glue Program at 36th EORTC-NCI-AACR Symposium

BOSTON, Oct. 9, 2024 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced it will present preclinical data from the Company's mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR Symposium, taking place October 23-25, 2024, in Barcelona, Spain. Presentation details are as follows: Title: Targeting the CBM signalosome with a MALT1 scaffolding inhibitor for treatment of NFkB driven solid tumors Poster Session: Molecular Targeted Agents Session Date and Time: Wed., Oct. 23, 2024, 12:00-19:00 CEST Abstract Number: 105 About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is a clinical-stage biotechnology company that is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

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