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 / Active, not recruiting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.

NCT05131022 / Recruiting临床1期

A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults With Relapsed/Refractory B-cell Malignancies

This is a first-in-human Phase 1a/1b multicenter, open-label study designed to evaluate the safety and anti-cancer activity of NX-5948 in patients with advanced B-cell malignancies.

开始日期2022-04-13

申办/合作机构

Nurix Therapeutics, Inc.

100 项与 NX-5948 相关的临床结果

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100 项与 NX-5948 相关的转化医学

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100 项与 NX-5948 相关的专利（医药）

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项与 NX-5948 相关的文献（医药）

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).

项与 NX-5948 相关的新闻（医药）

2024-11-20

·GlobeNewswire-Health Care

Nurix Therapeutics Receives PRIME Designation from the European Medicines Agency for NX-5948 for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia

The PRIME initiative provides enhanced support to developers of promising medicines to optimize development plans and accelerate evaluation Pivotal trials of NX-5948 are planned to initiate in 2025 SAN FRANCISCO, Nov. 20, 2024 (GLOBE NEWSWIRE) -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with cancer and inflammatory diseases, today announced that the European Medicines Agency (EMA) has granted PRIME designation for NX-5948, a highly selective degrader of Bruton’s tyrosine kinase (BTK), for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) after at least a BTK inhibitor and a BCL-2 inhibitor. To be eligible for PRIME, medicines must target an unmet medical need and show potential benefit for patients based on early clinical data. “PRIME designation for NX-5948 is an important recognition of the unmet patient need in CLL, particularly in the growing number of patients whose cancer has progressed following BTK inhibitor and BCL2 inhibitor therapy,” said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. “This designation follows encouraging safety and efficacy data from our ongoing Phase 1 clinical trial, demonstrating early promise of clinical benefit as well as mechanistic data supporting the activity of NX-5948 independent of mutations that confer resistance to covalent and non-covalent BTK inhibitors.” The PRIME initiative, launched by the EMA in 2016, offers early, proactive and enhanced support to developers of promising medicines to optimize development plans and accelerate evaluation so these medicines can reach patients faster. About NX-5948NX-5948 is an investigational, orally bioavailable, brain penetrant, small molecule degrader of BTK. NX-5948 is designed to specifically eliminate BTK, a key growth signaling protein in B cells, through degradation by the ubiquitin proteasome system of the cell. NX-5948 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Nurix has previously reported that NX-5948 is highly potent against a range of tumor cell lines that are resistant to current BTK inhibitor therapies, an important consideration in heavily pretreated CLL/SLL patient populations. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022). About Nurix Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of innovative small molecules and antibody therapies based on the modulation of cellular protein levels as a novel treatment approach for cancer, inflammatory conditions, and other challenging diseases. Leveraging extensive expertise in E3 ligases together with proprietary DNA-encoded libraries, Nurix has built DELigase, an integrated discovery platform, to identify and advance novel drug candidates targeting E3 ligases, a broad class of enzymes that can modulate proteins within the cell. Nurix’s drug discovery approach is to either harness or inhibit the natural function of E3 ligases within the ubiquitin-proteasome system to selectively decrease or increase cellular protein levels. Nurix’s wholly owned, clinical stage pipeline includes targeted protein degraders of Bruton’s tyrosine kinase, a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B, an E3 ligase that regulates activation of multiple immune cell types including T cells and NK cells. Nurix is headquartered in San Francisco, California. For additional information visit http://www.nurixtx.com. Forward-Looking Statements This press release contains statements that relate to future events and expectations and as such constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. When or if used in this press release, the words “anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,” “may,” “outlook,” “plan,” “predict,” “should,” “will,” and similar expressions and their variants, as they relate to Nurix, may identify forward-looking statements. All statements that reflect Nurix’s expectations, assumptions or projections about the future, other than statements of historical fact, are forward-looking statements, including, without limitation, statements regarding the potential advantages and therapeutic benefits of NX-5948, including its potential role in the treatment of patients whose cancer has progressed following BTK inhibitor and BCL2 inhibitor therapy or its role in addressing mutations that confer resistance to covalent and non-covalent BTK inhibitors; and the potential benefits of PRIME designation. Forward-looking statements reflect Nurix’s current beliefs, expectations, and assumptions. Although Nurix believes the expectations and assumptions reflected in such forward-looking statements are reasonable, Nurix can give no assurance that they will prove to be correct. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and changes in circumstances that are difficult to predict, which could cause Nurix’s actual activities and results to differ materially from those expressed in any forward-looking statement. Such risks and uncertainties include, but are not limited to: (i) the risks inherent in the drug development process, including the unexpected emergence of adverse events or other undesirable side effects during clinical development; (ii) uncertainties related to the timing and results of clinical trials; (iii) the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; (iv) whether Nurix will be able to successfully complete clinical development for, obtain regulatory approval of and ultimately commercialize NX-5948; (v) whether Nurix will be able to fund its research and development activities and achieve its research and development goals; (vi) the impact of economic and market conditions and global and regional events on Nurix’s business and clinical trials; (vii) whether Nurix will be able to protect intellectual property and (viii) other risks and uncertainties described under the heading “Risk Factors” in Nurix’s Quarterly Report on Form 10-Q for the fiscal period ended August 31, 2024, and other SEC filings. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. The statements in this press release speak only as of the date of this press release, even if subsequently made available by Nurix on its website or otherwise. Nurix disclaims any intention or obligation to update publicly any forward-looking statements, whether in response to new information, future events, or otherwise, except as required by applicable law. Contacts: Investors Jason Kantor, Ph.D.Nurix Therapeuticsir@nurixtx.com Elizabeth Wolffe, Ph.D.Wheelhouse Life Science Advisorslwolffe@wheelhouselsa.com Media Aljanae ReynoldsWheelhouse Life Science Advisorsareynolds@wheelhouselsa.com

临床1期

2024-11-19

·GlobeNewswire-Health Care

Nurix Therapeutics Presents Preclinical Data from Two Autoimmune and Inflammatory Disease Programs, NX-5948 and GS-6791, at ACR Convergence 2024

Nov. 17, 2024 -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with cancer and inflammatory diseases, today announced the presentation of preclinical data, including mechanism of action and relevant disease models, from two pipeline programs: NX-5948 and GS-6791. NX-5948 is Nurix’s proprietary, orally available, brain penetrant Bruton’s tyrosine kinase (BTK) degrader, which is being developed for the potential treatment of inflammation and autoimmune diseases in addition to its ongoing Phase 1b trial in patients with B-cell malignancies. GS-6791 is a selective, orally bioavailable degrader of interleukin-1 receptor-associated kinase 4 (IRAK4), which is being developed in collaboration with Gilead Sciences for the potential treatment of rheumatoid arthritis and other inflammatory diseases. These data were presented in two posters at ACR Convergence 2024, the annual meeting of the American College of Rheumatology (ACR), being held November 14–19, 2024, in Washington, D.C. “The preclinical data presented at ACR Convergence underscore the exceptional potential of our targeted protein degradation strategy compared to kinase inhibition for both BTK and IRAK4, which are critical targets in inflammatory and autoimmune diseases, and support continued advancement of these drug candidates into clinical studies,” said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. “These programs showcase the capability of Nurix’s DELigase platform to generate potent best-in-class degrader drug candidates with the potential to deliver superior efficacy in several inflammatory diseases.” BTK mediates signaling downstream of the B cell receptor (BCR), toll-like receptors (TLRs), and Fc receptors (FcRs), making it an attractive therapeutic target in antibody-mediated autoimmune and inflammatory diseases. BTK has been shown to have both kinase and scaffold activities that are key to its function. Targeting BTK can reduce the production of new antibodies and mitigate the inflammation induced by existing antibodies, addressing key challenges in inflammatory and autoimmune diseases. In a poster titled: NX-5948, a Clinical-Stage BTK Degrader, Achieves Deep Suppression of BCR, TLR, and FcR Signaling in Immune Cells and Demonstrates Efficacy in Preclinical Models of Arthritis and Other Inflammatory Diseases, data illustrate the potential benefit of the BTK degrader NX-5948, which is equivalent or superior to inhibition of BTK across multiple mechanistic studies and models of inflammatory diseases. In primary B cells, NX-5948 promotes rapid degradation of BTK and more potently suppresses proximal BCR signaling and BCR- and TLR-mediated B cell activation than current BTK inhibitors under development. In a model of established collagen-induced arthritis, oral administration of NX-5948 achieves equal or superior improvement of clinical scores and deeper suppression of plasma cell numbers compared to BTK inhibitors. NX-5948 also demonstrates efficacy in several other models of inflammatory diseases including antibody-induced glomerulonephritis (a model of lupus nephritis), autoimmune lymphoproliferative syndrome (ALPS, a second model of lupus-like disease), passive cutaneous anaphylaxis (a model of allergic response including chronic spontaneous urticaria), and experimental autoimmune encephalitis (a model of multiple sclerosis). IRAK4 plays a critical role in TLR- and interleukin-1 family receptor (IL-1R) signaling to induce inflammatory responses. Like BTK, IRAK4 has both kinase and scaffold functions, the latter of which have been shown to be particularly critical in IL-1 and TLR-mediated signaling across diverse cell types. GS-6791, a targeted protein degrader of IRAK4, provides a differentiated mode of action compared with inhibition of kinase activity. In a poster titled: IRAK4 Degrader GS-6791 Inhibits TLR and IL-1R-Driven Inflammatory Signaling, and Ameliorates Disease in a Preclinical Arthritis Model, data demonstrate that GS-6791 is a potent degrader of IRAK4 in vitro and in vivo across a range of cell types. In PK/PD models GS-6791 inhibits IL-1- and TLR-induced cytokine release and results in deeper reduction of human B cell and synovial fibroblast cytokine responses compared to IRAK4 kinase inhibitors. In a preclinical model of arthritis, orally administered GS-6791 demonstrates robust, dose-dependent efficacy. The poster presentations are available online in the Scientific Resources section of the Nurix Therapeutics website under Posters and Presentations. About NX-5948: NX-5948 is an investigational, orally bioavailable degrader of BTK that is currently being evaluated in a Phase 1a/b clinical trial in adults with relapsed or refractory B-cell malignancies. Additional information on the Phase 1a/b clinical trial can be accessed at www.clinicaltrials.gov (NCT05131022). About GS-6791 (previously NX-0479): GS-6791 is a potent, selective, oral IRAK4 degrader. Degradation of IRAK4 by GS-6791 has potential applications in the treatment of rheumatoid arthritis and other inflammatory diseases. Nurix’s collaboration partner, Gilead Sciences, is responsible for conducting IND-enabling studies and advancing this program to clinical development. Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of innovative small molecules and antibody therapies based on the modulation of cellular protein levels as a novel treatment approach for cancer, inflammatory conditions, and other challenging diseases. Leveraging extensive expertise in E3 ligases together with proprietary DNA-encoded libraries, Nurix has built DELigase, an integrated discovery platform, to identify and advance novel drug candidates targeting E3 ligases, a broad class of enzymes that can modulate proteins within the cell. Nurix’s drug discovery approach is to either harness or inhibit the natural function of E3 ligases within the ubiquitin-proteasome system to selectively decrease or increase cellular protein levels. Nurix’s wholly owned, clinical stage pipeline includes targeted protein degraders of Bruton’s tyrosine kinase, a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B, an E3 ligase that regulates activation of multiple immune cell types including T cell and NK cells. Nurix is headquartered in San Francisco, California. For additional information visit http://www.nurixtx.com. The content above comes from the network. if any infringement, please contact us to modify.

临床研究

2024-11-15

·医药速览

口服蛋白水解靶向嵌合体汇总，基于性质的优化

学以致用侃侃而言 RSC Med Chem 2024, Nov. 7th DOI: 10.1039/D4MD00769G 蛋白质水解靶向嵌合体（PRTOTACs）是一种靶向蛋白降解的新兴治疗策略，它们将靶标蛋白（POI）与E3连接酶紧密结合，并诱导参与泛素-蛋白酶体系统（UPS）以促进靶向蛋白质降解。近日，RSC Med Chem上刊载了一篇总结性研究，通过分析处于临床中的PROTACs实体分子的物理化学性质，汇总了PROTACs各组成部分的优化，以及对于实现口服生物利用度所面临的困难和挑战，并根据作者在这一领域的经验提出了一些珍贵的指导性意见和建议。主要内容 (1) 临床中的PROTACs (2) 口服生物利用度开发中的挑战 (3) 值得注意的陷阱提示 (4) 总结与展望，及往期相关精彩回顾 01 临床中的PROTACs PROTACs等靶向降解剂是一种“事件驱动”的治疗策略，其选择性地从细胞中去除靶标蛋白质。相比于传统的基于“占位驱动”的蛋白质功能抑制策略，PROTACs等靶向降解剂具有几个优势： (1)药理学上，PROTACs等靶向降解剂有可能提供更加完整的蛋白质功能封锁（如去除支架活性），因此，更有可能概括基因敲除实验的效果。简单地说，PROTACs等靶向降解剂不仅阻断了信号传导，而且通过分解细胞传播信号所需的机制，消除了细胞传播信号的能力； (2)细胞只能通过产生新的蛋白质来恢复功能，因此，药理学受到蛋白质的再合成率以及药物药效学的影响，从而提供了延长作用时间的可能性； (3) PROTAc机制中POI与E3组分之间必要的相互作用，为异构体之间（如，取决于三元复合物的形成和/或可用的表面赖氨酸残基）和组织内（如，取决于E3表达水平）的选择性提供了额外的机会；因此，这种药物实体已经出现，便被证明对于患者具有良好的耐受性和有效性，并已有多个实体分子进入后期临床研究。据统计，截至2024年7月，已有13种结构已公开的PROTACs进入临床试验阶段。这些PROTACs大多数用于肿瘤相关适应症，其中一种用于治疗炎症；两种因战略规划原因而停止（ARV-110、KT-413）。就E3连接酶配体而言，其中有12种携带CRBN配体，口服给药。而仅有一种需要静脉注射（IV）的DT-2216，携带VHL配体。如下图。图片源自RSC Med Chem 这些处于临床阶段的PROTACs实体的物化性质统计如下表。其中，携带CRBN配体的PROTACs分子量在711~958 Da；亲脂性（pH7.4时的LogD值）为1.4~4.8；色谱极性表面积（ePSA）为107~146 Å 2。图片源自RSC Med Chem 而计算出的分子亲脂性LogP和极性表面积tPSA的预测结果分散更为广阔：其中LogP为-0.6~6.8；tPSA范围为96~238 Å 2。此外氢键受体HBA为9~20；氢键供体HBD均≤5。如下图A，通过雷达图更形象地展示了临床口服PROTACs的物化性质空间（蓝色区域）在所有特性方面都超出了Lipinski五规则（Ro5）和Veber关于可旋转键（RotB）和极性表面积（PSA）（绿色区域）的经验指南，仅HBD除外。图片源自RSC Med Chem 上图B绿色条形图显示了小分子的可接受的性质范围，同时与临床PROTACs分子做了对比。在亲脂性方面，一些PROTACs突破了小分子LogP（≤5）和LogD（1~3）的极限。值得注意的是，ePSA的值（107~141 Å2）比tPSA （96~238 Å2）的范围窄得多，这表明这可能是口服PROTACs设计的更有价值的指南。尽管超出了先前确定的物理化学空间限制，口服给药仍然是首选的给药途径，专门为血液病癌症开发的DT2216和KT-413除外。以上每一种PROTACs都是经历了广泛的优化后，以实现药理学和物化性质的最佳平衡的结果。而PROTACs模块化、三组件的特性（POI配体、E3配体、连接子），其设计的技巧在于平衡单个部件组分的特征，从而使最终PROTACs的整体特性处于可接受的空间内。就POI配体而言：强效，较少的暴露HBD 许多PROTACs针对靶标POI改良的抑制剂/拮抗剂进行设计。这些抑制剂或拮抗剂通常是高效的配体片段基序，在其溶剂区安装输出载体，用以连接到E3结合基序片段。此外，这些配体大多数是中性的，而非酸性或碱性，并且氢键供体HBD≤1。以上几个PROTACs中也有几个例外，如ARV-393、NX-2127、KT-413、NX-5948，整体分子分别包含3、4、4、5个HBD，但分子内氢键可能屏蔽了其中的几个HBD。就E3连接酶配体而言：CRBN配体最流行在已经揭示了分子结构的临床PROTACs中，上面已提到，除了DT-2216以外，均是携带了CRBN配体。如下图，使用最广泛的CRBN配体包括来自免疫调剂亚胺类药物（IMiDs）沙利度胺、和来那度胺。这两者均具有高级性、高效、低分子量、并且在基本结合药效团中只有一个HBD。此外，它们对外排转运体缺乏敏感性，使其成为PROTACs的理想选择，特别是在实现口服生物利用度上。图片源自RSC Med Chem 而与IMiD类配体相关的安全性问题（如致畸性、血液毒性等），也可以解释为什么PROTACs最初的治疗适应症主要是肿瘤领域。也许正是因为这一点，当前正在出现不同于IMiD类的由新型CRBN配体组成的PROTACs。就连接体而言：胺基碱及富含环型基序片段占主导除了极个别例外，如CFT-1946，这些临床阶段的PROTACs的连接体的共同特征是存在一个叔胺碱，以及哌啶、哌嗪、或氮杂啶都行。在一些特定的情况下，哌啶的碱度似乎随着氟取代（CFT-8634）或氧取代（ARV-393、KT-474）的加入而有所缓和，使其碱度不超过所有口服PROTACs的预测值pKa=9.1。而静脉给药的PROTACs，如DT-2216，具有非常高的预测亲脂性（LogP=15.0）；然而，这降低到低得多的LogD=3.9，可能是由于其两性离子电荷所致；其高试验极性为193 Å2，比其他口服PROTACs的ePSA值高出52 Å2，比相关bRo5口服药物venetoclax的ePSA值高出31 Å2，似乎反映了这种两性离子。口服PROTACs的另一个共同之处是使用环状基序作为构象约束，所有实例在连接体中至少包含两个环，有些甚至三个环。在灵活性方面，10个实例在环之间包含亚甲基作为间隔剂，只有BMS986365具有乙氧基3-原子间隔剂。此外，CFT-1946具有最刚性的连接体，以酰胺键连接哌啶和螺环。而KT-474具有最大的非环组分，具有4-原子丙炔醚间隔，但即使这样也相对刚性，这表明构象约束是PROTACs的重要设计考虑因素。一些研究也表明富环的、刚性连接体可以产生更高的细胞靶标降解能力和更高的代谢稳定性。也因此，可旋转键仅略高于Ro5依从性口服药物经验指导的上限。而其中一个明显的例外则是DT-2216，具有29个可旋转键，高度灵活的连接体仍然可以产生强效的降解物，并且适用于静脉给药的PROTACs。 02 口服生物利用度的挑战 PROTACs分子由三个组分构成的结构特征使其在物化特性和口服生物利用度等方面面临着诸多挑战。 EARLY R&D 2.1、最严格的HBD，口服PROTACs设计的关键首先，构建分子量MW低于~700Da的PROTACs具有挑战性。这种对Lipinski的MW经验规则的违反，通常也会伴随着维持其它Ro5标准（如HBA、HBD、LogP）和其它物化特性的限制（如，PSA、可旋转键等）。尽管如此，如上一单元所示，也有不少临床中的PROTACs分子是可以生物利用的，尤其是在人类中达到有效的暴露水平。随着越来越多的试验数据的积累，以及对关键理化性质的分析总结，一些新的bRo5经验指导出现，并必将越来越成熟和精准。例如，Arvinas和AstraZeneca都强调了限制口服吸收的或溶剂暴露的HBDs（eHBDs）数量的重要性。两个团队都得出这样的结论：虽然物化性质，如分子量、亲脂性、分子极性和HBA等可以超过口服药物的Ro5限制，但eHBD≤2这个标准是一个严格有效的设计标准。对于bRo5化学空间里的大环类药物，相关研究发现，酰胺类HBD的上限为2个，而总体正式的HBD上限为7个，这相对宽松了许多，大概也是因为分子内氢键屏蔽约束的结果。回到PROTACs来说，也或许也解释了为什么CRBN配体在临床PROTACs组成中更受青睐，因为这些基序片段小、有效且只有一个eHBD。因此，尽管挑战重重，通过合理使用分子属性可支配限制，是设计PROTACs的关键，特别是最严格的方面，即HBD。 EARLY R&D 2.2、三元复合物本身的问题带来的挑战尽管PROTACs能够有效地形成促进表面赖氨酸泛素化的三元复合物，然则其也仅能针对靶向蛋白质发挥降解功能。这种三聚体复合物的建模是非常具有挑战性的。这是因为，可能存在多种三元复合物构象，并且并非所有这些构象都能导致有效的靶标降解，这无疑阻碍了基于结构的PROTACs设计。相比于传统小分子设计程序，PROTACs的设计要考虑分子大小、“POI-连接体-E3”组分之间的构象和物理化学性质相互作用，这意味着有更多的“化学等式”需要优化。考虑到构成可及的三元配合物的不确定性，以及它位于正确的物化空间，因此，生产“活性”PROTACs的复杂性将会导致一系列设计和合成方面的挑战。针对这么多不确定性，一种解决办法是通过生产“库”，用来探索广阔的化学空间，从而实际地解决以经验方式存在的巨大的组合优化。 EARLY R&D 2.3、变形嵌合体的挑战 PROTAC的三元组成和分子大小，使理解其构象比传统小分子更具挑战性。一般，预先组织分子使其具有生物活性构象，以减少结合时的熵损补偿是一种行之有效的策略。然而，对于PROTACs分子，配体可以获得更大程度的构象自由度，再加上三元复合物的构象可塑性和不确定性，使得准确确定要模仿的“生物活性”构象具有挑战性。利用核磁共振技术，结合分子动力学模拟来了解PROTACs的构象行为及其对渗透率的影响是目前的一种方法。在极性溶剂和非极性溶剂中观察到的差异性，为构象集成、端到端反折叠和潜在的分子内氢键（IMHB）提供了证据。研究发现，与未折叠的配对对比，CRBN和VHL安装的PROTACs的溶剂依赖性（即“变色龙”效应）分子内折叠，增加了它们的被动细胞通透性。 EARLY R&D 2.4、PROTACs体外试验生产数据的分析对于PROTACs领域的工作人员来说，另一个挑战是使用基于传统小分子优化程序配置的体外分析生成对PROTACs有意义的数据的能力。如前面所提，PROTACs分子大，通常是亲脂性的碱，有粘附在实验仪器/蛋白质/膜上的倾向，导致渗透性和蛋白质结合试验回收率很低。传统的摇瓶法亲脂性分析通常难以达到LogD＞4，而且溶解度通常低于检测极限，这使得在缺乏数据的情况下筛选候选药物极具挑战性。而且，作者还根据经验提到，代谢稳定性测定（肝细胞和微粒体孵育）产生可靠的值，在淘汰不稳定的PROTACs方面是没有价值的。色谱法（ChromologD、ePSA）扩大了亲脂性和暴露极性的可测范围，并允许在一系列化合物中对化合物进行排序。此外，已有报道将色谱方法与计算机方法相结合来生成更多相关的3D描述符，以提高设计口服可用PROTACs的成功率。 03 陷阱提示在整个PROTACs中整合CRBN结合实体，特别是IMiDs，会带来需要监测的相关安全风险。这些风险可能与以下有关：与IMiDs非常相似，相应的PROTACs可以作为分子胶降解剂，并导致许多蛋白质降解，从而诱发毒理学效应；例如，值得注意的一个新的底物，GSPT1，一个平移终止因子。其的无意降解降低了蛋白质合成的速率，导致细胞毒性，同时伴有POI的明显和误导性降解。总的来说，这些发现强调需要细致的对照实验来询问PROTACs的作用机制（MoA），从而促进其优化为有效和安全的药物。从发现阶段到体内PROTACs的评估，一个关键教训是了解它们的代谢命运的重要性。即使对于代谢相对稳定的PROTACs，也可能产生极性更强、亲脂性更低和未结合清除率更低的片段。然后，它们可以竞争与POI或E3结合，并降低三元复合物形成的有效性，从而降低体内疗效。此外，即使精心设计的利用CRBN的PROTAC的代谢物，没有分子胶降解剂（MGD）活性，理论上也可以作为MGD，从而引入MGD相关的安全责任。因此，在当前临床试验执行过程中对此类风险进行评估，无疑将使科学界了解利用CRBN的PROTACs用于非肿瘤适应症的适用性。 04 总结与展望 PROTACs目前已经从初始的肿瘤适应症领域向其它领域扩展，但主要还是在肿瘤领域，并且当前临床中的PROTACs还是以利用CRBN作为首选的E3连接酶。初步数据也证实，人类的生物功效和口服生物利用度也是可以实现的。通过已公开的数据，得到的结论是它们在一些结构上（如碱性、富环连接体）和关键物化特性上（如eHBD≤2）等方面表现出了统一性的特征，并具有一定的指导意义。往期相关精彩回顾 A Rebiew of the Past 站在靶向蛋白降解临床获批的风口，耶鲁大学Craig M. Crews教授最新展望 2024-11-09 JACS|耶鲁大学Crews教授报道肿瘤组织特异性靶向降解剂在PROTACs耐药性问题中的应用 2024-08-29 J Med Chem | 阿斯利康揭示蛋白水解靶向嵌合体降解剂（PROTACs）口服生物利用度设计的黄金规则 2024-08-07 JMC最新总结，反褶积：寻找新型靶向蛋白降解E3连接酶 2024-07-12 EJMC |含氮杂环在靶向降解剂PROTACs连接子中的应用和挑战 2024-06-04 关于PROTACs、分子胶等靶向降解剂（TPD）的高通量筛选 2024-05-24 往期链接 “小小疫苗”养成记 | 医药公司管线盘点人人学懂免疫学 | 人人学懂免疫学（语音版）综述文章解读 | 文献略读 | 医学科普 | 医药前沿笔记 PROTAC技术 | 抗体药物 | 抗体药物偶联-ADC 核酸疫苗 | CAR技术 | 化学生物学温馨提示医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群加作者微信（yiyaoxueshu666）或者扫描公众号二维码添加作者，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。简单操作即可星标⭐️医药速览，第一时间收到我们的推送 ①点击标题下方“医药速览” ②至右上角“...” ③点击“设为星标

蛋白降解靶向嵌合体临床结果

100 项与 NX-5948 相关的药物交易

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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	荷兰	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	荷兰	Nurix Therapeutics, Inc.	2022-04-13
弥漫性大B细胞淋巴瘤	临床1期	英国	Nurix Therapeutics, Inc.	2022-04-13
滤泡性淋巴瘤	临床1期	美国	Nurix Therapeutics, Inc.	2022-04-13
滤泡性淋巴瘤	临床1期	荷兰	Nurix Therapeutics, Inc.	2022-04-13
滤泡性淋巴瘤	临床1期	英国	Nurix Therapeutics, Inc.	2022-04-13
套细胞淋巴瘤	临床1期	美国	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


ASH2024	N/A	复发性慢性淋巴细胞白血病	-	NX-5948 50 mg	齋廠醖糧顧鬱簾鹽醖襯(顧壓襯範鑰鏇築鑰衊鹹) = 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); pulmonary embolism (1 case, not deemed treatment related) 廠製積衊製壓膚築鏇選 (夢顧憲簾鏇觸齋餘蓋繭 )	-	2024-12-09
ASH2024	N/A	复发性慢性淋巴细胞白血病	-	NX-5948 100 mg		-	2024-12-09
NCT05131022 (GlobeNewswire) 人工标引	临床1期	巨球蛋白血症	79	NX-5948	襯鹹顧獵夢獵憲製夢蓋(網網選鬱夢鏇繭願膚網) = 鬱積築製簾鑰衊艱餘壓餘醖窪鹽構淵夢製觸簾 (壓鹽鹽鬱遞糧鹽觸醖鬱 ) 更多	积极	2024-10-19
NCT05131022 (EHA2024) 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	艱蓋遞醖餘構鏇簾鏇鬱(鏇夢餘憲壓壓願顧顧鏇) = none 衊糧壓糧膚窪憲獵獵蓋 (範壓繭鹽鹽鑰醖範遞淵 ) 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	獵築鹹齋壓淵積醖鹽顧(襯鹹積簾鏇衊願壓製壓) = 餘鬱齋衊餘願鏇廠顧鏇窪鏇顧選壓簾鑰鬱齋鹹 (膚選齋醖窪鏇構糧遞廠 ) 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	鑰鹹鏇獵蓋糧齋窪構憲(廠製壓蓋觸簾艱淵窪鏇) = 艱獵廠築艱膚構壓願願觸膚獵鏇築蓋衊餘顧窪 (糧製廠窪築鏇醖鹽艱醖 ) 更多	积极	2023-12-11