A Phase 1, Open-Label Study in Healthy Volunteers to Evaluate the Relative Bioavailability of NX-5948 Tablets Compared to Capsules, and the Effect of Food and an Acid-reducing Agent on the Pharmacokinetics of NX-5948

This is a 2-cohort, fixed-sequence, 3-period, relative bioavailability, food-effect, and drug-drug interaction study. It is an open-label study evaluating the relative bioavailability of NX-5948 tablets compared to capsules, and the effect of food and an acid-reducing agent on the pharmacokinetics (PK) of NX-5948.

开始日期2024-11-30

申办/合作机构

Nurix Therapeutics, Inc.

NCT06691828

/ Completed临床1期

A Phase 1, Open-Label, 2-Period, Fixed-Sequence Study to Assess the Absolute Bioavailability, Absorption, Metabolism, Excretion, and Mass Balance of [14C]-NX-5948 in Healthy Males

This is a Phase 1, 2-period, open-label, single-dose, fixed-sequence study to assess the absolute bioavailability, absorption, metabolism, excretion, and mass balance of [14C]-NX-5948. Period 1 will analyze PD (pharmacodynamics) and exploratory biomarkers. Period 2 will analyze total radioactivity and metabolite profiling.

开始日期2024-11-01

申办/合作机构

Nurix Therapeutics, Inc.

NCT06593457

/ Completed临床1期

A Phase 1, 2-Part, Placebo-Controlled, Double-Blinded Study to Assess the Effect of Food and Drug-Drug Interaction of Fluconazole on the Pharmacokinetics of NX-5948

This is a Phase 1, 2-part double-blinded (with respect to NX-5948/placebo), placebo-controlled study. Part 1 is a randomized, 3 period cross-over food-effect (FE) and drug-drug interaction (DDI) study. Part 2 is a single-period PK evaluation study.

开始日期2024-08-20

申办/合作机构

Nurix Therapeutics, Inc.

100 项与 Bexobrutideg 相关的临床结果

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100 项与 Bexobrutideg 相关的转化医学

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100 项与 Bexobrutideg 相关的专利（医药）

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项与 Bexobrutideg 相关的文献（医药）

2025-05-01·AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS

Bruton Tyrosine Kinase Degraders

Review

作者: Sabakhtarishvili, Giorgi ; Tabbara, Imad A. ; Bajwa, Omer ; Alshebli, Mouza

Bruton tyrosine kinase (BTK) is a key enzyme involved in B-cell development and signaling, making it a crucial target in the treatment of B-cell malignancies, such as chronic lymphocytic leukemia and non-Hodgkin lymphoma. While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance—both intrinsic and acquired—poses a significant challenge, often associated with BTK mutations like C481S. To address this, novel BTK degraders have been developed, leveraging proteolysis-targeting chimeras to selectively degrade both wild-type and mutant BTK forms. This approach offers a promising strategy to overcome BTKi resistance.Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials. NRX-0492 demonstrated over 90% BTK degradation with sustained pharmacodynamic effects, whereas BGB-16673 achieved clinical responses in 67% of patients with relapsed/refractory B-cell malignancies. Similarly, NX-5948 and NX-2127 showed potent BTK degradation, with NX-2127, in addition, targeting immunomodulatory proteins, resulting in partial and stable responses in chronic lymphocytic leukemia and non-Hodgkin lymphoma patients. HZ-Q1060, a preclinical candidate, displayed rapid and sustained BTK degradation in vivo. Early-phase trials of ABBV-101 and AC676 are also showing promising results.These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy.

2024-06-01·Bioorganic chemistry

Research progress of PROTACs for neurodegenerative diseases therapy

Review

作者: Fang, Yuanying ; Yang, Zunhua ; Li, Huilan ; Cai, Zhifang

Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.

2023-03-30·Blood

The cat-and-mouse game of BTK inhibition.

Communications

作者: Portelinha, Ana ; Wendel, Hans-Guido

In this issue of Blood, Zhang et al¹ report the preclin. efficacy of a new Bruton tyrosine kinase (BTK) degrader mol. (NRX-0492, a close relativeOf the clin. compounds NX-2127 and NX-5948)² to overcome BTK inhibitor resistance.The authors show that NRX-0492 degrades wild-type and C481 mutant BTK, resulting in significant single-agent activity against chronic lymphatic leukemia (CLL) patient-derived xenografts in vivo.¹A closely related compound, NX-2127,² is now in clin. trials in B-cell malignancies (NCT04830137).

106

项与 Bexobrutideg 相关的新闻（医药）

2025-05-14

·GlobeNewswire-Health Care

Nurix Therapeutics Announces Presentations of Clinical Data at the 30th European Hematology Association Congress and the 18th International Conference on Malignant Lymphoma

SAN FRANCISCO, May 14, 2025 (GLOBE NEWSWIRE) -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, today announced that data from the Company’s ongoing Phase 1a/b clinical trial of bexobrutideg (NX-5948) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and Waldenström macroglobulinemia will be presented at two major upcoming scientific conferences. Data will be featured in two posters at the European Hematology Association 2025 Congress (EHA 2025), taking place June 12–15, 2025, in Milan, Italy, and in an oral presentation and poster at the 18th International Conference on Malignant Lymphoma (18-ICML), to be held June 17–21, 2025, in Lugano, Switzerland. EHA 2025 Presentation Details: Title: Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in relapsed refractory CLL: updated findings from an ongoing Phase 1a StudyPresenting author: Zulfa Omer, M.D., Assistant Professor Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USASession title: Poster Session 1 Session date and time: Friday, June 13 (18:30 - 19:30 CEST)Abstract ID: PF571 Title: Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase (BTK) degrader, shows high clinical activity and tolerable safety in an ongoing Phase 1a/b study in patients with Waldenström macroglobulinemia Presenting author: Dima El-Sharkawi, M.B., B.S., M.A., Ph.D., MRCP FRCPath, Consultant Haematologist, Royal Marsden NHS Foundation Trust, Sutton, UKSession title: Poster Session 2 Session date and time: Saturday, June 14 (18:30 - 19:30 CEST)Abstract ID: PS1883 18-ICML Oral Presentation Details: Title: Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in relapsed refractory CLL: updated findings from an ongoing Phase 1a StudyPresenter: Alexey Danilov, M.D., Ph.D., Marianne and Gerhard Pinkus Professor in Early Clinical Therapeutics, Co-Director of Toni Stephenson Lymphoma Center, City of Hope National Medical Center, Duarte, CA, USASession title: 18: New DrugsSession date and time: Saturday, June 21 (9:30 CEST).Abstract ID: 093 18-ICML Poster Presentation Details: Title: Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase (BTK) degrader, shows high clinical activity and tolerable safety in an ongoing Phase 1a/b study in patients with Waldenström macroglobulinemia Presenting author: David Lewis, M.D., Consultant Hematologist, Derriford Hospital; Associate Professor, Derriford Hospital, Plymouth, UKSession title: Poster Session (Odd numbered posters)Session date and time: Thursday, June 19 (10:00-18:00 CEST)Abstract ID: 437 About Bexobrutideg (NX-5948)Bexobrutideg is an investigational, orally bioavailable, brain penetrant, small molecule degrader of BTK. Bexobrutideg is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022). About Nurix Therapeutics, Inc.Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, the next frontier in innovative drug design aimed at improving treatment options for patients with cancer and inflammatory diseases. Nurix’s wholly owned, clinical stage pipeline includes degraders of Bruton’s tyrosine kinase (BTK), a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B (CBL-B), an E3 ligase that regulates activation of multiple immune cell types including T cells and NK cells. Nurix also is advancing multiple potentially first-in-class or best-in-class degraders and degrader antibody conjugates (DACs) in its preclinical pipeline. Nurix’s partnered drug discovery pipeline consists of preclinical stage degraders of IRAK4 and STAT6, as well as multiple additional programs under collaboration agreements with Gilead Sciences, Inc., Sanofi S.A. and Pfizer Inc., within which Nurix retains certain options for co-development, co-commercialization and profit sharing in the United States for multiple drug candidates. Powered by a fully AI-integrated discovery engine capable of tackling any protein class, and coupled with unparalleled ligase expertise, Nurix’s dedicated team has built a formidable advantage in translating the science of targeted protein degradation into clinical advancements. Nurix aims to establish degrader-based treatments at the forefront of patient care, writing medicine’s next chapter with a new script to outmatch disease. Nurix is headquartered in San Francisco, California. For additional information visit http://www.nurixtx.com. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995 and other federal securities laws. Any statements contained herein that do not describe historical facts, including, but not limited to, statements regarding the planned timing for the provision of updates and findings from the clinical trial of bexobrutideg at EHA 2025 and ICML 2025, are forward-looking statements that involve risks and uncertainties that could cause actual results to differ materially from those discussed in such forward-looking statements. Such risks and uncertainties include, among others, the risks described under the heading “Risk Factors” in Nurix’s Quarterly Report on Form 10-Q for the quarter ended February 28, 2025, and subsequent filings with the SEC. Any of these risks and uncertainties could materially and adversely affect Nurix’s business and results of operations, which could, in turn, have a significant and adverse impact on Nurix’s stock price. Nurix cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. Nurix undertakes no obligation to update publicly any forward-looking statements to reflect new information, events or circumstances after the date they were made or to reflect the occurrence of unanticipated events. Contacts: InvestorsKris Fortner.Nurix Therapeutics, Inc.Kfortner@nurixtx.com Elizabeth Wolffe, Ph.D.Wheelhouse Life Science Advisorslwolffe@wheelhouselsa.com MediaAljanae ReynoldsWheelhouse Life Science Advisorsareynolds@wheelhouselsa.com

临床1期

2025-04-28

·精准药物

Nat. Rev. Cancer∣靶向蛋白降解在癌症治疗中的应用与进展

近年来，靶向蛋白降解（Targeted Protein Degradation, TPD）作为一种新兴的治疗策略，在癌症治疗领域展现出巨大潜力。TPD的核心理念是通过重新编程细胞内的蛋白质降解机制，实现对特定致病蛋白的精准降解。它与传统的抑制剂类药物不同，并非直接阻断蛋白质的功能，而是借助细胞自身的降解系统——泛素 - 蛋白酶体系统（Ubiquitin–Proteasome System, UPS），清除目标蛋白质。这一创新性的策略不仅能够提高药物的选择性和疗效，还有望克服传统治疗手段的诸多局限。泛素-蛋白酶体系统（UPS）UPS是细胞内主要的蛋白质降解系统，负责80-90%的细胞内蛋白质的降解。它通过泛素分子标记需要降解的蛋白质，随后将其送入蛋白酶体进行分解。这一过程高度复杂且精细调控。E3泛素连接酶在其中扮演着关键角色，它能够特异性识别目标蛋白，并将其与泛素分子连接起来。如图1所示：首先，泛素分子通过E1激活酶被激活，随后转移到E2结合酶上，最终在E3连接酶的介导下，泛素分子被连接到目标蛋白上。被泛素标记的蛋白质随后被送入26S蛋白酶体，进行降解。这一系统不仅负责清除受损、错误折叠的蛋白质，还在细胞周期调控、信号传导等生命活动中发挥着关键作用。例如，在缺氧条件下，缺氧诱导因子-1α（HIF-1α）能够逃避免泛素化降解，从而启动一系列适应缺氧的生理反应。这种对蛋白质降解的精确调控，为TPD技术提供了理论基础。图1.泛素-蛋白酶体系统的机制PROTACs和分子胶降解剂目前，TPD领域主要分为两大类技术：异双功能蛋白降解靶向嵌合体（PROTACs）和分子胶降解剂（Molecular Glue Degraders, MGDs）。这两类技术虽然在化学结构和作用机制上有所不同，但都旨在通过促进目标蛋白与E3连接酶之间的相互作用，诱导目标蛋白的泛素化和降解。PROTACs：PROTACs是由两个独立的配体通过化学链连接而成的异双功能分子。其中一个配体能够结合目标蛋白，另一个配体则能够结合E3连接酶。当PROTACs与目标蛋白和E3连接酶同时结合时，会形成一个三元复合物，使目标蛋白靠近E3连接酶，从而促进泛素转移和蛋白质降解。图2清晰地展示了PROTACs的作用机制。以dBET6为例，它能够将BET蛋白（BRD2–BRD4）与CUL4–DDB1–CRBN E3连接酶复合体连接起来，从而实现对BET蛋白的降解。目前，已有多种PROTACs进入临床试验，如针对雄激素受体（AR）的ARV-110和ARV-766，以及针对雌激素受体（ER）的AC682和ARV-471等，这些药物在前列腺癌和乳腺癌的治疗中展现出良好的应用前景。图2.PROTACs的作用机制分子胶降解剂：与PROTACs不同，分子胶降解剂通常不直接与目标蛋白或E3连接酶单独结合，而是通过增强目标蛋白与E3连接酶之间的现有表面互补性，促进它们之间的相互作用。例如，免疫调节亚胺药物（IMiDs）如沙利度胺、来那度胺和泊马度胺就是典型的分子胶降解剂。它们能够增强CRBN（Cereblon）E3连接酶与一系列目标蛋白（如IKZF1和IKZF3）之间的相互作用，导致目标蛋白的降解。图3展示了分子胶降解剂的作用方式。以pomalidomide为例，它通过增强CRBN与目标蛋白之间的亲和力，促进目标蛋白的泛素化和降解。目前，来那度胺和泊马度胺等分子胶降解剂已在多发性骨髓瘤的治疗中获得广泛应用，并取得了显著的临床效果。图3.分子胶降解剂的作用机制新兴的降解模式除了PROTACs和分子胶降解剂，科学家们还不断探索新的降解策略，以进一步拓展TPD技术的应用范围。以下是一些新兴的降解模式：间接降解剂：巧妙的 “间接引导者”间接降解剂通过将目标蛋白的相互作用蛋白招募到E3连接酶，从而间接实现目标蛋白的降解。例如，CR8能够将CDK12招募到DDB1适配器上，CDK12进而招募细胞周期蛋白K到DCAF底物受体通常占据的位置，诱导细胞周期蛋白K 的泛素化（图4）。图4.间接降解剂的作用机制分子内二价胶：创新的“分子内桥梁”分子内二价胶（Intramolecular Bivalent Glues, IBGs）通过同时结合目标蛋白的两个结构域，将其排列成能够增强与E3连接酶相互作用的构象，从而实现目标蛋白的降解。例如，IBG1能够同时结合BRD4的两个溴结构域BD1和BD2，并将其排列成与DCAF16 E3连接酶高亲和力结合的构象（图5）。这一创新的降解模式为设计新型TPD分子提供了新的思路。图5.分子内二价胶的作用机制降解尾：巧妙的“化学修饰”降解尾是指通过在目标蛋白结合剂上添加简单的化学基团，将其转化为高效的降解剂。例如，GNE-0011通过在其表面暴露区域添加一个轻度亲电的丙炔胺尾，实现了对BRD2和BRD4的降解（图6）。这种策略为快速筛选和优化降解剂提供了便利。图6.引入降解尾的作用机制核激素受体降解剂：精准的“受体调控”核激素受体降解剂通过与核激素受体结合，诱导受体的构象变化，从而触发其泛素化和降解。例如，选择性雌激素受体降解（SERDs）如fulvestrant和elacestrant能够通过置换雌激素受（ER）配体结合和激活功能2（AF2）结构域中的螺旋12，触发ER通过RNF111介导的途径降解（图7）。这些降解剂在乳腺癌的治疗中展现出良好的应用前景。图7.核激素受体降解剂的作用机制SUMO依赖性降解：独特的“修饰触发”SUMO依赖性降解通过诱导目标蛋白的SUMO修饰，使其被SUMO靶向E3连接酶（STUbLs）识别并泛素化降解。例如，WRN抑制剂HRO671能够诱导WRN蛋白发生180°的构象变化，被SUMO E3连接酶PIAS4识别并泛素化，随后通过蛋白酶体降解（图8）。这一降解模式为研究蛋白质修饰与降解的关系提供了新的视角。图8.SUMO依赖性降解的作用机制抑制剂诱导的蛋白不稳定化：巧妙的 “功能干扰”一些原本设计为抑制剂的小分子化合物，通过诱导目标蛋白的不稳定化，促使其降解。例如，BI-3802能够诱导BCL6聚合形成丝状结构，增强其与E3连接酶 SIAH1的相互作用，从而实现BCL6的降解（图9）。这种现象为发现新型降解剂提供了意外的线索。图9.抑制剂诱导的蛋白不稳定化的作用机制临床应用：与传统的抑制剂类药物相比，TPD药物具有以下显著优势：（一）更高的选择性和效力：通过诱导目标蛋白与E3连接酶之间的特异性相互作用TPD药物能够实现对目标蛋白的精准降解，减少对非目标蛋白的影响。例如SD-36能够选择性降解STAT3，尽管其亲本抑制剂SI-109对STAT1和STAT4也具有一定的亲和力。（二）低剂量和持续效果：TPD药物通过催化机制发挥作用，能够在亚化学计量的情况下诱导目标蛋白的降解，从而在较低剂量下实现持久的治疗效果。例如，ACBI3 能够在降解13种常见的KRAS突变体时，展现出比其亲本抑制剂更强的效力和更持久的MAPK信号抑制作用。（三）克服传统治疗的耐药性：TPD药物能够同时破坏目标蛋白的多种功能，包括其获得的新功能（如BTK的新异性支架功能），从而克服传统治疗的耐药性。例如，PROTACs如NX-2127和NX-5948能够降解BTK，有效杀死对抑制剂耐药的细胞。临床试验中的 TPD 药物：目前，多项 TPD 药物的临床试验正在如火如荼地进行中(见下表)。目前TPD技术面临的挑战：（一）药物设计的复杂性TPD药物的设计需要综合考虑目标蛋白与E3连接酶之间的相互作用、药物的化学稳定性和生物利用度等多个因素。例如，PROTACs的设计通常需要在目标蛋白和E3连接酶之间找到合适的化学连接链，以确保三元复合物的稳定性和降解效率。此外，药物的理化性质（如分子量、溶解性、渗透性等）也会影响其药代动力学和药效学特性。（二）耐药性的产生与传统药物类似，TPD药物也可能面临耐药性问题。例如，CRBN基因的突变可能导致来那度胺等分子胶降解剂的耐药性。此外，E3连接酶复合物的其他亚基发生突变或表达量变化，也可能影响TPD药物的疗效。（三）药物的药代动力学和药效学特性TPD药物的药代动力学和药效学特性（如吸收、分布、代谢、排泄等）对其临床应用具有重要影响。例如，PROTACs由于其较大的分子量和复杂的化学结构，往往具有较差的口服生物利用度和血脑屏障穿透能力。这些特性可能限制药物在体内的分布和作用时间，影响其治疗效果。（四）安全性和毒性问题TPD药物的安全性和毒性也是需要重点关注的问题。由于TPD药物通过诱导目标蛋白的降解发挥作用，其潜在的非目标效应（如对其他蛋白质的非特异性降解）可能导致不良反应。此外，药物对E3连接酶的过度激活或抑制也可能干扰细胞内的正常蛋白质稳态，引发毒性反应。结论靶向蛋白降解技术作为癌症治疗领域的一项重大突破，为患者带来了新的希望和选择。从PROTACs和分子胶降解剂的经典模式，到新兴的降解策略，TPD技术不断拓展着我们的视野和可能性。尽管其在发展过程中面临诸多挑战，但通过科学家们的不懈努力和创新，我们有理由相信，TPD技术将在未来的癌症治疗中扮演越来越重要的角色，开启癌症治疗的新篇章。原文链接：https://doi.org/10.1038/s41568-025-00817-8声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体

2025-04-09

·药明康德

年度十大“明星分子”榜单出炉

▎药明康德内容团队编辑编者按：近日，知名产业媒体猎药人（Drug Hunter）发布了2024年度明星分子榜单。从数以万计的研究论文中，猎药人依据技术创新、科学贡献、潜在临床价值以及独创性等多个维度，结合读者和评审专家的综合意见，最终选取十款明星分子入围榜单。经过读者投票，Vertex公司开发的“first-in-class”止痛药suzetrigine名列榜首。在这十大明星分子中，药明康德化学业务平台很高兴能为其中多款提供赋能服务，推动创新落地。未来，我们期待能进一步助力更多合作伙伴，加速创新疗法的研发，为全球病患提供更多治疗选择。Suzetrigine：口服NaV1.8离子通道抑制剂图片来源：猎药人官网Suzetrigine是Vertex Pharmaceuticals公司开发的“first-in-class”口服NaV1.8离子通道选择性抑制剂。电压门控钠离子通道是介导神经元释放动作电位的重要离子通道。人类遗传学研究显示，编码NaV1.8的基因的失活性突变让个体对疼痛不敏感，而功能获得性突变则会导致持续疼痛。Vertex的研究人员通过分析离子通道开关过程中快速发生的构象变化，发现了新的潜在结合位点。Suzetrigine对NaV1.8离子通道的选择性与其它NaV相比最终达到了3万到4万倍。Suzetrigine在今年1月获得美国FDA的批准（商品名Journavx），用于治疗成人中度至重度急性疼痛。Vertex公司的新闻稿指出，Journavx是20多年来首个获得FDA批准用于治疗急性疼痛的新机制药物。它有望在缓解患者疼痛的同时，减少与服用阿片类止痛药相关的潜在副作用和上瘾风险。Zoldonrasib（RMC-9805）：KRAS G12D突变体选择性共价抑制剂图片来源：猎药人官网RMC-9805是Revolution Medicines公司开发的KRAS G12D突变体选择性共价抑制剂。它基于该公司独有的三元复合体（Tri-Complex）抑制剂平台，与伴侣蛋白cyclophilin A结合后，可以与激活状态下的KRAS突变体以高亲和力形成三元复合体。RMC-9805同时能够与KRAS G12D突变体中第12位天冬氨酸形成交联，从而抑制KRAS G12D突变体的活性。去年10月，Revolution Medicines公布了RMC-9805的首个临床试验结果。在携带KRAS G12D突变的经治胰腺导管腺癌（PDAC）患者中，接受2期临床试验推荐剂量RMC-9805治疗患者的客观缓解率达30%，疾病控制率为80%。Daraxonrasib（RMC-6236）：非共价泛KRAS分子胶抑制剂图片来源：猎药人官网RMC-6236是Revolution Medicines公司开发的另一款泛KRAS抑制剂，同样利用了其三元复合体抑制剂平台，将cyclophilin A与激活状态下的KRAS突变体“粘合”在一起达到抑制KRAS活性的效果。去年12月公布的最新临床试验数据显示，在携带KRAS G12X突变的转移性PDAC患者中，接受每日一次300毫克剂量RMC-6236治疗患者的中位无进展生存期（PFS）为8.8个月，携带任何类型RAS突变的患者中，中位PFS为8.5个月。KRAS G12X突变患者的6个月生存率达100%，携带任何类型RAS突变患者的6个月生存率为97%。目前，RMC-6236正在两项3期临床试验中接受评估，用于治疗PDAC和非小细胞肺癌（NSCLC）患者。Icotrokinra：口服IL-23受体多肽抑制剂图片来源：PubChemIcotrokinra是Protagonist Therapeutics和强生（Johnson & Johnson）公司联合开发的IL-23受体口服多肽抑制剂。Icotrokinra能够以个位数的皮摩尔级亲和力与IL-23受体结合，并对人类T细胞中的IL-23信号转导产生强效的选择性抑制作用。近日公布的关键性3期临床试验结果显示，每日一次icotrokinra显著改善了中度至重度斑块型银屑病患者的皮肤状况，并具有良好的安全性。第16周时，65%的icotrokinra组患者达到研究者总体评估（IGA）评分为0/1（皮肤症状清除或几乎清除），50%的患者达到银屑病面积与严重程度指数（PASI）改善至少90%（PASI 90），而安慰剂组在这两个指标的数值分别仅为8%和4%。到第24周，患者缓解率进一步提高，74%的患者达到IGA评分为0/1，46%达到IGA 0分；65%的患者达到PASI 90，40%达到PASI 100。Laroprovstat（AZD0780）：口服PCSK9小分子抑制剂图片来源：猎药人官网AZD0780是阿斯利康（AstraZeneca）公司开发的潜在“first-in-class”口服PCSK9小分子抑制剂。PCSK9是降低低密度脂蛋白胆固醇（LDL-C）已经验证的靶点，不过目前的获批疗法均需要患者定期接受注射。口服PCSK9调节剂可能给患者提供更便捷的用药方式。去年5月，阿斯利康公布了AZD0780的首个人体临床试验结果。数据显示，在未经治疗的高胆固醇血症患者中，AZD0780在基于瑞舒伐他汀治疗的基础上，显示出52%（95% CI：57%，45%）的LDL-C水平显著下降，与基线相比患者的LDL-C总体下降幅度达78%。此外，比较进食与空腹服药的初步数据表明AZD0780对进食具有灵活性。未报告严重不良事件，AZD0780显示良好的耐受性。目前AZD0780处于2期临床开发阶段。HRO761：别构WRN抑制剂图片来源：猎药人官网HRO761是诺华（Novartis）公司开发的非共价别构WRN抑制剂。WRN是DNA解旋酶RecQ家族的成员之一。DNA解旋酶是一类在DNA或RNA复制过程中起到催化双链DNA或RNA解开的生物酶，参与了DNA复制、修复、转录、重组以及端粒的维持等细胞代谢过程，在维持染色体的稳定性中具有重要的作用。此前研究发现，WRN和微卫星不稳定性高（MSI-H）癌症之间具有合成致死的关系。HRO761通过与WRN在D1和D2解旋酶结构域的界面上发生别构结合，使WRN锁定在非活性构象中。HRO761抑制WRN的活性可选择性导致MSI-H癌细胞的DNA损伤以及抑制癌细胞的生长。此外，HRO761还能在MSI-H细胞中导致WRN的降解。目前，HRO761治疗实体瘤的1期临床试验正在进行中。VVD-214：共价别构WRN抑制剂图片来源：猎药人官网VVD-214是由拜耳（Bayer）公司旗下的Vividion Therapeutics和罗氏（Roche）联合开发的共价别构WRN抑制剂。WRN是MSI-H肿瘤的合成致死靶点。研究人员使用化学蛋白质组学（chemoproteomics）赋能的发现方法，筛选出这款WRN抑制剂。它在MSI-H结直肠癌细胞系和异种移植肿瘤模型中表现出强力抗癌活性。目前罗氏正在1期临床试验中评估它用于治疗MSI-H癌症的效果。Inavolisib：口服PI3Kα突变体选择性抑制剂和降解剂图片来源：猎药人官网Inavolisib是由罗氏旗下基因泰克（Genentech）开发的PI3Kα抑制剂，具有高度PI3Kα突变体选择性，并且能够特异性触发PI3Kα蛋白突变体的降解。通过这种独特的双重作用机制，inavolisib可能为激素受体（HR）阳性/人类表皮生长因子受体2（HER2）阴性、PIK3CA突变的晚期乳腺癌患者提供耐受良好、持久的疾病控制和潜在改善的结局。它在2024年10月获得FDA的批准（商品名Itovebi），与CDK4/6抑制剂Ibrance（palbociclib）和氟维司群（fulvestrant）联用，治疗肿瘤携带PIK3CA突变、内分泌治疗耐药、HR阳性、HER2阴性局部晚期或转移性乳腺癌成年患者，这些患者在接受辅助内分泌治疗时或完成辅助内分泌治疗后疾病复发。罗氏表示，它具有成为“best-in-class”PI3Kα抑制剂的潜力。KT-474（SAR444656）：口服IRAK4靶向蛋白降解剂图片来源：猎药人官网KT-474（SAR444656）是由Kymera Therapeutics和赛诺菲（Sanofi）联合开发的潜在“first-in-class”的IRAK4降解剂。IRAK4是myddosome蛋白复合体中的关键组分，通过白细胞介素-1（IL-1）和toll样受体（TLR）参与调控免疫反应的信号传导过程。IL-1和toll样受体在启动针对入侵病原体的免疫反应中扮演着关键角色。IRAK4是一种支架激酶，处于先天性免疫反应与适应性免疫反应的交汇点，通过其激酶活性和支架功能执行多重作用。KT-474利用靶向蛋白降解完全消除IRAK4，会影响其激酶和支架功能，因此有可能实现广泛、耐受性良好的抗炎作用，提供多种免疫炎症疾病的新治疗途径。此前公布的1期临床试验结果显示，在治疗特应性皮炎时，KT-474表现出可喜的活性。中重度患者在接受治疗28天后，瘙痒程度减轻63%，湿疹面积和严重度指数（EASI）评分下降36%。赛诺菲公司计划扩大正在进行的化脓性汗腺炎和特应性皮炎的2期临床试验，以更快地将这款创新疗法推进至关键性临床研究阶段。NX-5948：口服布鲁顿氏酪氨酸激酶（BTK）降解剂图片来源：猎药人官网NX-5948是Nurix公司开发的BTK靶向蛋白降解剂，它可以穿越血脑屏障，并且可降解野生型和突变型BTK蛋白。去年10月公布的早期临床试验结果显示，接受NX-5948治疗的9名复发/难治性华氏巨球蛋白血症（WM）患者中，7例患者（77.8%）出现客观缓解，两例患者病情稳定（22.2%）。所有7例缓解均在8周的首次评估中观察到，其中5例患者仍在接受治疗，2例患者治疗时间超过一年。不论患者基线MYD88和CXCR4的突变状态如何，均观察到应答。参考资料：[1] Top 12 Most Popular Drug Hunter Case Studies of 2024. Retrieved March 12, 2025, from https://drughunter.com/articles/top-12-most-popular-drug-hunter-case-studies-of-2024[2] AACR San Diego 2024: New Drugs on the Horizon + RMC-6236. Retrieved March 12, 2025, from https://drughunter.com/articles/aacr-san-diego-2024-new-drugs-on-the-horizon-rmc-6236[3] AZD0780, an oral PCSK9 inhibitor demonstrated significant LDL-C reduction on top of statin in Phase I trial. Retrieved March 12, 2025, from https://www.astrazeneca.com/media-centre/medical-releases/azd0780-an-oral-pcsk9-inhibitor-demonstrated-significant-ldl-c-reduction-on-top-of-statin-in-phase-i-trial.html[4] An Oral Small Molecule PCSK9 Inhibitor Disclosed by AstraZeneca. Retrieved March 12, 2025, from https://drughunter.com/molecule/azd0780[5] A Covalent Allosteric WRN Helicase Inhibitor Stemming from Chemoproteomics Screening. Retrieved March 12, 2025, from https://drughunter.com/molecule/vvd-214-ro7589831[6] Molecule One-Pager: KT-474 (SAR444656). Retrieved March 12, 2025, from https://drughunter.com/resource/molecule-one-pager-kt-474-sar444656[7] Icotrokinra results show potential to set a new standard of treatment in plaque psoriasis. Retrieved March 12, 2025, from https://www.jnj.com/media-center/press-releases/icotrokinra-results-show-potential-to-set-a-new-standard-of-treatment-in-plaque-psoriasis[8] The Highly Potent and CNS-Active NX-5948 Shows BTK Degradation in Patients. Retrieved March 12, 2025, from https://drughunter.com/molecule/nx-5948[9] Revolution Medicines Presents Initial Data from RMC-9805 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Retrieved March 12, 2025, from https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-rmc-9805-monotherapy[10] Molecules of the Year Nominees. Retrieved March 18, 2025, from https://drughunter.com/molecules-of-the-month/2024/2024[11] Suzetrigine (VX-548): The 2024 Molecule of the Year. Retrieved April 9, 2025, from https://drughunter.com/articles/suzetrigine-vx-548-the-2024-molecule-of-the-year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

临床2期

100 项与 Bexobrutideg 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
慢性淋巴细胞白血病	临床1期	美国	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	法国	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	意大利	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	荷兰	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	波兰	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	西班牙	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	瑞士	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	英国	Nurix Therapeutics, Inc.	2022-04-13
弥漫性大B细胞淋巴瘤	临床1期	美国	Nurix Therapeutics, Inc.	2022-04-13
弥漫性大B细胞淋巴瘤	临床1期	法国	Nurix Therapeutics, Inc.	2022-04-13

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05131022 (NX-5948-301, ASH2024) 人工标引	临床1期	慢性淋巴细胞白血病末线 \| 三线	34	NX-5948	窪顧構襯範網淵積網遞(願繭鏇艱醖廠壓夢鏇鑰) = Most common TEAEs were: purpura/contusion (44.1%, no Gr≥3); thrombocytopenia (23.5%, 2.9% Gr≥3); petechiae (29.4%, no Gr≥3); fatigue (20.6%, no Gr≥3); neutropenia (17.6%, 14.7% Gr≥3; pts with up to Gr 4 cytopenias were eligible for study participation); rash (23.5%, no Gr≥3, 2.9% SAE); headache (23.5%, no Gr≥3).There was no new onset atrial fibrillation/flutter or hypertension. 齋選鹹觸壓觸鏇構壓願 (獵願顧膚壓範鑰餘餘糧 ) 更多	积极	2024-12-09
NCT05131022 (GlobeNewswire) 人工标引	临床1期	巨球蛋白血症	79	NX-5948	襯範鑰積鹽衊衊膚膚齋(窪選獵築鏇鬱壓窪觸積) = 鹹鏇簾憲觸繭簾糧鹽憲鑰簾艱鏇獵積鑰鏇鹹艱 (鏇蓋糧夢鏇壓積糧廠網 ) 更多	积极	2024-10-19
NCT05131022 (EHA 12024 \| EHA 22024) 人工标引	临床1期	慢性淋巴细胞白血病 \| B细胞恶性肿瘤	46	NX-5948	繭襯顧膚餘範積糧鹽製(廠網壓鬱願餘獵齋壓膚) = none 範鹽鏇鹹遞廠壓獵襯觸 (築憲膚鑰艱壓蓋網糧範 ) 更多	积极	2024-05-14
NCT05131022 (Biospace) 人工标引	临床1期	慢性淋巴细胞白血病	7	NX-5948	襯網鏇製繭糧膚鑰壓積(壓鹹鏇選網窪願餘鬱簾) = 鏇網顧憲夢廠艱願齋繭鏇廠觸積膚鬱網觸憲簾 (齋網觸淵廠壓構鹽構顧 ) 更多	积极	2024-01-16
NCT05131022 (NX-5948-301, ASH2023) 人工标引	临床1期	B细胞淋巴瘤三线	14	NX-5948	繭獵鑰構遞鹹選衊鹹鑰(築獵憲膚壓鹹鬱廠憲艱) = 鏇觸選範積觸窪襯簾鬱壓淵壓壓壓艱築顧鑰鑰 (觸網壓憲夢鹽夢鹹網淵 ) 更多	积极	2023-12-11