This phase I trial studies the side effects and best dose of ubiquitin-activating enzyme (UAE) inhibitor TAK-243 (TAK-243) in treating patients with a solid tumor that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic) and in patients with lymphoma. TAK-243 is a drug that binds to and inhibits the ubiquitin-activating enzyme, an enzyme that is more active on cancer cells than healthy cells, inhibiting tumor cell proliferation and survival.

开始日期2025-03-24

申办/合作机构

National Cancer Institute

NCT03816319

/ Recruiting临床1期IIT

A Phase 1 Study of TAK-243 for Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts

This phase I trial studies the side effects and best dose of TAK-243 in treating patients with acute myeloid leukemia or myelodysplastic syndromes with increased blasts that has come back (relapsed) or that is not responding to treatment (refractory). TAK-243 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

开始日期2025-03-12

申办/合作机构

National Cancer Institute

NCT02045095

/ Terminated临床1期

A Phase 1, Open-Label, Multicenter, Dose Escalation Study to Assess the Safety and Tolerability of MLN7243, an Inhibitor of Ubiquitin-Activating Enzyme (UAE), in Adult Patients With Advanced Solid Tumors

The purpose of this study is to evaluate safety and tolerability (establish maximum tolerated dose [MTD], inform the recommended phase 2 dose [RP2D], and identify the dose-limiting toxicities [DLTs]) of MLN7243.

开始日期2014-01-31

申办/合作机构

Millennium Pharmaceuticals, Inc.

100 项与 TAK-243 相关的临床结果

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100 项与 TAK-243 相关的转化医学

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100 项与 TAK-243 相关的专利（医药）

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项与 TAK-243 相关的文献（医药）

2025-08-01·LEUKEMIA

Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome

Article

作者: Cunningham, Claire ; Sampson, Avery M ; Starczynowski, Daniel ; Hueneman, Kathleen M ; Choi, Kwangmin ; Philbrook, Sophia Y ; Clough, Courtnee A ; Greis, Kenneth D

Abstract:

VEXAS syndrome is a clonal hematopoietic disorder characterized by hyperinflammation, bone marrow failure, and high mortality. The molecular hallmark of VEXAS is somatic mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. These mutations induce a protein isoform switch, but the mechanisms underlying disease pathogenesis remain unclear. Here, we developed a human cell model of VEXAS syndrome by engineering the male monocytic THP1 cell line to express the common UBA1M41V mutation. We found that mutant UBA1M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating key features of VEXAS. Moreover, proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1M41V cells, with alterations in inflammatory and stress-response pathways. Functional studies demonstrated that UBA1M41V cells were highly sensitive to genetic or pharmacological inhibition of E1 ubiquitin enzymes. Treatment with the E1 enzyme inhibitor TAK-243 preferentially suppressed colony formation of UBA1M41V cells as compared to WT cells. Moreover, UBA1M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1, suggesting that UBA6 may compensate for UBA1 dysfunction in UBA1M41V cells. Targeting UBA6 using shRNA or the UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 in UBA1M41V cells. Phytic acid selectively impaired growth and colony formation in UBA1M41V cells while sparing WT cells, highlighting a potential therapeutic vulnerability. Together, these findings establish a novel human model of VEXAS syndrome, identify key roles for UBA1 and UBA6 in disease pathogenesis, and demonstrate that UBA6 inhibition represents a promising therapeutic strategy for selectively targeting UBA1 mutant clones.

2025-06-01·SLAS Discovery

Combinatorial screen with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell type tumor spheroids

Article

作者: Coussens, Nathan P ; Doroshow, James H ; Silvers, Thomas ; Takebe, Naoko ; Sanchez, Phillip R ; Dexheimer, Thomas S ; Hollingshead, Melinda G ; Teicher, Beverly A ; Chen, Li

Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Dysregulation of apoptosis pathways is a hallmark of cancer, allowing malignant cells to evade cell death and proliferate uncontrollably. Targeting apoptosis pathways has emerged as a promising therapeutic strategy in cancer treatment, aiming to restore the balance between cell survival and death. The MDM2 inhibitor alrizomadlin, the Bcl-2/Bcl-xL inhibitor pelcitoclax, and the IAP family inhibitor dasminapant were evaluated both individually and in combinations with standard of care and investigational anticancer small molecules in a spheroid model of solid tumors. The multi-cell type tumor spheroids were grown from human endothelial cells and mesenchymal stem cells combined with human malignant cells that were either established or patient-derived cell lines from the NCI Patient-Derived Models Repository. The malignant cell lines were derived from a range of solid tumors including uterine carcinosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (MPNST), pancreas, ovary, colon, breast, and small cell lung cancer. Interactions were observed from combinations of the apoptosis pathway targeted agents. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively.

2025-05-08·JOURNAL OF MEDICINAL CHEMISTRY

ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation

Article

作者: Ali, Eslam M. H. ; Albrecht, Lauren ; Trader, Darci J. ; Loy, Cody A. ; Kragness, Kate A. ; Harris, Timothy J. ; Seabrook, Laurence J.

The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.

项与 TAK-243 相关的新闻（医药）

2025-08-02

·精准药物

【JMC】中国学者报道一类新型、强效IKZF1/2/3三重分子胶降解剂

近日，来自国家应急防控药物工程技术研究中心，国家安全特需药品全国重点实验室的研究团队与华北理工大学研究团队合作在国际权威药物化学期刊《Journal of Medicinal Chemistry》上发表了一篇题为“Discovery of Novel Potent Triple IKZF1/2/3 Degraders for the Treatment of Hematological Cancers”的研究论文（DOI: 10.1021/acs.jmedchem.5c01086）。该研究通过系统的理性设计及构效优化、体外/体内机制验证及小鼠模型疗效评估，获得全新酞嗪酮为骨架的新型强效IKZF1/2/3三重分子胶降解剂MGD-22，可显著抑制肿瘤生长（TGI达97.28%），无明显毒性，且与布鲁顿酪氨酸激酶（BTK）抑制剂和B细胞淋巴瘤-2（BCL-2）抑制剂联合使用时具有显著的协同效应。该研究为血液系统癌症治疗提供了新候选药物和多靶点降解策略，为克服现有度胺药物耐药性提供了的新解决方案。01 研究背景：传统度胺类药物的困境与突破方向分子胶降解剂是一类能够诱导蛋白质-蛋白质相互作用（PPI），利用人体内天然存在的泛素-蛋白酶系统特异性地靶向降解某种疾病相关蛋白的小分子化合物 [1]。血液肿瘤的发生与发展，常与造血细胞中关键转录因子的异常激活密切相关。其中，IKZF家族（IKZF1、IKZF2、IKZF3）作为重要的锌指转录因子，在造血系统发育和肿瘤细胞生存中起关键作用[2]。传统度胺类药物（IMiDs）如沙利度胺、来那度胺、泊马度胺通过招募CRBN形成 E3 连接酶复合物，诱导IKZF1、IKZF3等转录因子降解发挥作用，广泛用于血液系统癌症（如多发性骨髓瘤（MM）、急性髓系白血病（AML）、弥漫性大 B 细胞淋巴瘤（DLBCL）等）治疗，但现有 IMiDs 及下一代 CELMoDs（如 CC-220、CC-885、CC-82480）因结构相似性易引发耐药，其次血液毒性（如中性粒细胞减少、肝损伤）等问题限制临床应用，需开发新型 CRBN 调节剂以拓展治疗潜力 [3]。02 研究内容① 全新骨架先导物发现与结构优化从 160 余万个化合物中筛选出含戊二酰亚胺结构的候选分子，通过表型筛选发现phthalazinone（酞嗪酮）骨架（如 MGD-1f）相比传统邻苯二甲酰亚胺，能更高效结合CRBN与IKZF家族蛋白，同时诱导IKZF1/2/3降解，尤其对IKZF2的降解活性提升显著，而 IKZF2 在白血病干细胞存活、肿瘤进展中至关重要 [4]。MGD-1f在急性髓系白血病（MV-4-11）细胞中IC50 < 1 μM，且对IKZF2降解率（27.7%）显著高于泊马度胺（< 10%）。分子对接显示，MGD-1f 能占据CRBN与IKZF2的结合界面，促进三元复合物的形成。为提升MGD-1f的活性，研究团队开展“结构-活性关系（SAR）”分析，通过修饰分子结构增强与靶蛋白的相互作用：l环结构调整：将MGD-1f 酞嗪酮环中的碳氮双键（C=N）还原为单键（C-N），得到MGD-3a，增加分子柔性；进一步引入甲基（MGD-3b），利用疏水作用增强与CRBN的结合，对IKZF2降解率提升至48.4%，对多发性骨髓瘤（NCI-H929）细胞的IC50降至0.379 μM。l取代基优化：在酞嗪酮的5位引入芳香胺基团（如MGD-4），通过π-π堆叠作用增强与IKZF2的结合，对IKZF2降解率大于50%；延长侧链并引入甲基苯（MGD-15），对IKZF2降解率提升至70%，对弥漫性大B细胞淋巴瘤（WSU-DLCL-2）细胞的IC50降至0.172 μM；l侧链拓展：在MGD-15的结构基础上引入吗啉、哌嗪等基团，进一步增强与 IKZF2的π-π堆叠作用（如MGD-18），进一步增强对IKZF1/2/3的降解作用，对NCI-H929和WSU-DLCL-2细胞的IC50降至0.0299和0.0805 μM；(A) Substrate scope of glutarimide analogues, thalidomide, lenalidomide and pomalidomide in IKZF1, IKZF2 and IKZF3 in engineered HEK293T cells using the respective HiBit assays. Cells were treated with 1 μM concentration of each compound for 24 h. (B) The docking model of MGD-1f to the IKZF2 (orange)-CRBN (green) derived from the Protein Data Bank (PDB: 7LPS).② 高效抑制肿瘤，克服耐药性经过多轮优化最终获得MGD-22，通过独特的分子结构稳定结合CRBN，脂肪族叔胺与CRBN的Glu377形成盐桥，增强结合亲和力，进而招募 IKZF1/2/3实现“三重降解”，且活性达到纳摩尔级别。MGD-22抑制NCI-H929、MV-4-11、WSU-DLCL-2细胞增殖IC50值为0.005-0.009 μM，远优于传统药物，且对泊马度胺耐药的肿瘤细胞仍有效（IC50值为0.04-0.08 μM）。对正常细胞如外周血单核细胞（PBMCs）、原代B细胞毒性低，IC50 > 33 μM。Evaluation of analogues MGD-16 to MGD-22. (A) The binding mode of MGD-15 interacts to the IKZF2-CRBN. PDB ID: 7LPS. (B) IC50 values of Chemical structures of MGD-15-based derivates (MGD-16 to MGD-22), lenalidomide (Len) and pomalidomide (Pom) in NCI-H929, MV-4-11 and WSU-DLCL-2 cells for 96 h. (C) Substrate scope of analogues MGD-16 to MGD-22, lenalidomide (Len) and pomalidomide (Pom) in IKZF1, IKZF2 and IKZF3 in engineered HEK293T cells using the respective HiBit assays. (D) Model of IKZF2 (orange), CRBN (green), and MGD-22 projecting a π-π system cloud from an aromatic substitution. The model was derived from PDB: 7LPS. (E) Western blot analysis of Ikaros family members in NCI-H929 (left) and MV-4-11 (right) cells treated with indicated doses of MGD-20, MGD-21, MGD-22 and pomalidomide (Pom) for 24 h.③ 精准高效降解靶点，机制明确蛋白组及IKZFs-HiBit定量模型结果表明，MGD-22特异性诱导IKZF1/2/3降解，对IKZF1/2/3的半数降解浓度（DC50）值分别为8.33 nM、9.91 nM、5.74 nM，24小时内可降解超过90%的靶蛋白，选择性优异。CRBN敲除细胞中MGD-22丧失降解能力，蛋白酶体抑制剂（MG132），泛素激活酶（E1）酶抑制剂（TAK-243）或NEDD8 活化酶 (NAE) 抑制剂（MLN4924）阻断降解选择性降解，表明MGD-22通过Cullin-CRBN通路诱导IKZF1/2/3的降解。MGD-22 selectively induces significant degradation of Ikaros proteins. (A) Proteomics analysis of NCI-H929 cells treated for 4 h with MGD-22 (1 μM) or DMSO. (B) Heatmap showing the ratio of global neosubstrates in whole-proteome quantification. (C) Levels of IKZF1, IKZF2 and IKZF3 in engineered HEK293T (293T) cells with increasing doses of MGD-22 for 24 h as determined by IKZF1-, IKZF2- and IKZF3-HiBit assay, respectively. (D) Levels of IKZF1, IKZF2 and IKZF3 in engineered HEK293T cells with increasing treatment time of MGD-22 (1 µM) as determined by IKZF1-, IKZF2- and IKZF3-HiBit assay, respectively. MGD-22 induces significant degradation of Ikaros proteins via the Cullin-CRBN dependent pathway. (A) Viability of control vector and CRBN−/− NCI-H929 cells treated with MGD-22 for 96 h. (B) Western blot analysis of IKZF1, IKZF2 and IKZF3 degradation in NCI-H929 cells CRBN knockout, pre-treated with TAK-243 (1 µM), MLN4924 (1 µM) or MG132 (1 µM) for 1 h and treated with MGD-22 (1 µM) for 24 h. C. Viability assay performed in MV-4-11 cells treated with increasing doses of MGD-22 for 96 h in the absence and presence of pomalidomide (Pom, 10 µM). (D, E) Flow cytometry plot showing control vector and CRBN−/− NCI-H929 cells treated with indicated doses of MGD-22 or pomalidomide (Pom) for 3 days, and cells were stained with Annexin V-PE and DAPI (D). Apoptosis was measured by flow cytometry using Annexin V as a marker (E). ⑤ 体内疗效显著，药代性质及安全性良好在NCI-H929小鼠异种移植模型中，MGD-22（10mg/kg，口服）的肿瘤生长抑制率（TGI）达97.28%，显著优于传统药物泊马度胺（69.74%），肿瘤组织Western blot证实IKZF1/2/3降解。长期给药后，小鼠体重无明显下降，无严重毒性反应。MGD-22药代性质良好，口服生物利用度39.4%，达峰时间（Tmax）1.0 h，清除率和分布容积适中。MGD-22 exhibited high efficiency in MM tumor xenograft. (A) Treatment schedule for the NCI-H929 cells xenograft tumors model treated with vehicle, pomalidomide and MGD-22, respectively. (B, C) Immunodeficiency NOD/SCID mice transplanted with NCI-H929 cells were orally administrated vehicle control, pomalidomide (Pom) or MGD-22 with single doses of 3 mg/kg or 10 mg/kg for 14 days. The change of NCI-H929 tumor volume (B) and change of body weight (C) of all mice in each group were shown (n = 8 per group). (D) Tumor volumes and TGI after treatment for 14 days of each group in (B) are shown. (E, F) Representative images of H&E, Ki67, and cleaved-caspase 3 immunohistochemical (IHC) staining in harvested tumors from each group in (B) are shown (E). Histograms show the quantification of Ki67+ and cleaved-caspase 3+ cells (F). (G) Western blot analysis of CRBN, IKZF1, IKZF2 and IKZF3 in harvested tumors or their mixture (#M, n = 8) from each group were shown.⑥ 协同治疗增效，拓宽应用场景研究发现，MGD-22与现有靶向药物BTK抑制剂（伊布替尼）、BCL-2抑制剂（维奈托克）联合使用时，协同评分（SS）均超10，在弥WSU-DLCL-2模型中，TGI达92.69%，显著高于单药（MGD-2单药77.47%，伊布替尼单药46.71%）；与BCL-2抑制剂（维奈托克）联合TGI达97.76%，显著高于单药维奈托克（61.88%）且显著延长小鼠生存期。Synergetic effect of MGD-22 with standard therapeutic agents in inhibiting DLBCL cell growth. (A, B) Effect of MGD-22, Ibrutinib, Venetoclax or drug combination on viability of WSU-DLCL-2 cells (A). Three-dimensional synergy score heatmaps for MGD-22 plus Ibrutinib (left) or Venetoclax (right) in WSU-DLCL-2 cells calculated using SynergyFinder (B). (C) Treatment schedule for the WSU-DLCL-2 cells xenograft tumors model treated with vehicle, MGD-22, Ibrutinib, Venetoclax or drug combination. (D, F) NOD/SCID mice transplanted with WSU-DLCL-2 cells were orally administrated with single agent MGD-22, Ibrutinib, Venetoclax or combinational treatment of MGD-22 + Ibrutinib and MGD-22 + Venetoclax for 36 days. The change of WSU-DLCL-2 tumor volume (D) of all mice in each group were shown. Tumor volumes and TGI after treatment for 21 days of each group in (C) are shown (n = 7 per group). Change of body weight (F) of all mice in each group were shown (n = 7 per group). (G) Survival rates for mice treated as in (C) were shown (log-rank test; n = 7 per group). 03 研究总结：为血液肿瘤提供新的治疗策略本研究发现了一种新型强效IKZF1/2/3三靶点分子胶降解剂MGD-22，其在多种血液瘤细胞中展现出纳摩尔级IC50抑制活性，克服现有IMiDs耐药性并降低毒性，且与标准疗法联用展现显著协同效应，为血液肿瘤治疗提供候选药物。MGD-22的发现不仅验证了IKZFs三重降解策略的可行性，“骨架创新+精细修饰”的设计策略也为新一代分子胶降解剂的开发提供新思路。原文链接：https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01086参考文献(1). Wu H, Yao H, He C, Jia Y, Zhu Z, Xu S, et al. Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment. Acta Pharm Sin B. 2022;12(9):3548-66.(2). Chen Q, Shi Y, Chen Y, Ji T, Li Y, Yu L. Multiple functions of Ikaros in hematological malignancies, solid tumor and autoimmune diseases. Gene. 2019;684:47-52.(3). Feng Y, Hu X, Wang X. Targeted protein degradation in hematologic malignancies: clinical progression towards novel therapeutics. Biomark Res. 2024;12(1).(4). Park S-M, Cho H, Thornton AM, Barlowe TS, Chou T, Chhangawala S, et al. IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation. Cell Stem Cell. 2019;24(1):153-65.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↓

临床1期蛋白降解靶向嵌合体临床结果

2024-12-10

·药时代

【First-in-class药设系列】靶向GSPT1的分子胶设计及在抗胶质母细胞瘤中研究

扫码报名2024肝病新药联盟年会暨减重新药论坛！胶质母细胞瘤（Glioblastoma, GBM）是成人中最具侵袭性的原发性恶性脑肿瘤,其治疗方法主要包括手术、放疗，靶向治疗，免疫治疗和干细胞治疗等。由于GBM存在高度的异质性，通常有低的突变负担，并且其肿瘤微环境固有的免疫抑制性，使得传统的化疗和免疫疗法难以发挥预期效果。mTOR是雷帕霉素靶蛋白，其通过PI3K-AKT-mTOR信号通路或通过影响胶质母细胞瘤微环境在胶质母细胞瘤的发展中起着至关重要的作用。GSPT1作为调控蛋白翻译终止的关键蛋白，在胶质母细胞瘤中高度表达，并通过特定机制促进胶质母细胞瘤的进展。有研究表明，mTOR抑制剂耐药原因之一可能是由于GSK3β表达量降低引起，而GSPT1的降解会促使GSK3β的表达上调，有望克服其耐药。与此同时，mTOR的抑制能有效增强GSPT1降解剂活性，并且mTOR抑制和GSPT1降解在细胞翻译的始末具有协同作用。基于此，研究人员提出了一种利用分子胶技术将小分子抑制剂和分子胶降解剂特性整合到单一分子中的新策略。首先，通过结合多种mTOR抑制剂和E3泛素连接酶配体，结合分子胶的特点，研究人员选择刚性短的连接体构建双功能化合物库，通过多轮筛选，筛选出YB-2-43，它对胶质母细胞瘤细胞的增殖具有抑制作用。通过进一步的结构优化，最终获得mTOR抑制和GSPT1降解活性更好的双功能化合物YB-3-17。同时使用MLN0128（mTOR抑制剂）和SJ6986（GSPT1降解剂）治疗U87细胞，发现其抗肿瘤活性虽有提高，但仍逊于YB-3-17，这表明YB-3-17在同时干扰两个靶点时存在显著协同作用。基于torkinib与mTOR的共晶结构(PDB:4JT5)，研究人员使用mTOR对YB-3−17和MLN0128进行了分子动力学模拟，对接结果表明YB-3-17能够有效适应mTOR的激酶口袋，其琥珀酰亚胺环中的羰基基团与mTOR的LYS2306形成了强烈的氢键相互作用，这可能增强了其抑制活性。MMGBSA分析显示，YB-3-17与mTOR的亲和力较低，表明与MLN0128相比，YB-3−17是一个更稳定的配合物。此外，使用CRBN-CC885GSPT1的共晶结构(PDB:SHXB)，预测了YB-3-17的分子胶结合模式。将YB-3-17中的谷氨酰胺进行乙基化以得到YB-3-17-NEG，作为阴性对照组；其丧失了与CRBN的结合，并且降低对GSPT1的降解活性，但保留了较强的对下游mTOR磷酸化的抑制。经免疫共沉淀实验显示，在YB-3-17处理下，Flag-CRBN HeLa细胞中的GSPT1蛋白与mTOR相比显著富集，而MLN0128和阴性对照分子YB-3-17-NEG则没有达到这种效果，这些结果突出表明YB-3−17独特的作用机制，其选择性地增强GSPT1在目标细胞环境中的积累，并诱导CRBN和GSPT1之间形成紧密的次级复合体。研究人员对YB-3-17进行了进一步的生物学活性评估以及机制验证。YB-3-17以浓度和时间依赖性的方式显著抑制了U87细胞中S6K，4EBP1以及AKT蛋白的磷酸化水平，表明其抑制mTORC1/2复合物活性的能力。YB-3−17处理细胞6h可以观察到GSPT1明显降解。随后，研究发现，YB-3-17诱导的GSPT1降解可以被蛋白酶体抑制剂(卡非佐米、硼替佐米)、类泛素化抑制剂(MLN4924、MLN7243)和泊马度胺阻断，但不会被MLN0128阻断，这表明GSPT1的降解依赖于蛋白酶体系统而不是与mTOR的结合。这表明了YB-3-17通过蛋白酶体途径作用于GSPT1的特异性。激酶活性测定表明，YB-3-17的ICs0为0.22nM，优于mTOR抑制剂MLN0128。在生物学活性评估中，YB-3-17还展现出了对多种神经肿瘤细胞的增殖抑制作用，显著优于单靶点mTOR抑制剂、GSPT1降解剂以及它们的联合治疗。这一结果充分展示了YB-3-17通过双靶点协同作用所带来的治疗优势。相比单一靶点药物，YB-3-17能够同时作用于mTOR和GSPT1，可以更有效的抑制肿瘤细胞增殖。进一步，通过蛋白质组学和激酶谱实验评估YB-3-17的降解选择性和激酶抑制选择性，以此来评估其安全性。蛋白质组学分析显示，YB-3−17处理后GSPT1，GSPT2和SNUPN均有下调，但通过western blotting验证表明，YB-3−17并没有诱导GSPT2和SNUPN这两种蛋白的降解，这表明YB-3−17只显著降解GSPT1，而不影响其他细胞内蛋白，展现极好的降解选择性。同时，激酶谱实验显示，不同于MLN0128，YB-3−17不抑制对细胞生长至关重要的FGR、CSF1R （FMS）、LCK和LYNa等脱靶蛋白，进一步证实，YB-3-17在抑制mTOR活性时具有显著的选择性，未对多种常见的细胞生长相关激酶产生抑制作用。同时，在对小鼠进行的为期三天的连续给药研究中，MLN0128单次30 mg/kg剂量会导致小鼠死亡，而接受等量YB-3−17治疗的小鼠在整个研究期间保持良好的健康状况。这些数据表明，YB-3−17降低了脱靶效应的毒性，同时通过降解GSPT1和抑制mTOR增强了疗效。通过RNA测序分析，作者进一步探索YB-3-17的作用机制。KEGG分析显示，YB-3−17显著富集了与多种途径相关的基因，包括氨基酸合成、内质网蛋白质加工和胰岛素抵抗信号。这种广泛的活性表明YB-3-17对细胞过程的多方面影响。且通过火山图分析，YB-3-17处理后SENS2、DDIT4和CHAC1在mRNA水平上的显著上调，这些基因能够显著增强对mTOR的抑制活性。同时，YB-3−17还显示出大量富集与细胞凋亡（DDIT3）和p53信号通路（GADD45A）相关的基因。以上数据表明，YB-3-17通过影响更广泛的信号通路发挥抗肿瘤效应。在体内实验中，通过将U87细胞接种到雄裸鼠中建立了异种移植模型，随后，通过腹腔注射对小鼠进行治疗。与对照组相比，MLN0128和YB-3−17均能显著抑制肿瘤生长。然而，在相同剂量下，YB-3−17表现出更好的疗效。在10/20 mg/kg剂量下，YB-3−17几乎完全停止肿瘤生长，导致肿瘤消退，表明其体内抗肿瘤能力更强。并且，相比于MLN0128，不同剂量的YB-3-17处理小鼠后，小鼠状态良好。进一步在体内验证了YB-3−17抑制mTOR和降解GSPT1的能力。通过免疫印迹法分析腹腔注射指定剂量的YB-3−17,MLN0128后，裸鼠肿瘤细胞中GSPT1、cyclin D1、pS6K、pAKT和β-actin的变化，进一步证实了YB-3-17显著抑制mTOR下游蛋白的磷酸化，并以剂量依赖性方式降解GSPT1。综上，本研究提出了在一个小分子中同时实现mTOR抑制和GSPT1降解的双靶双机制小分子设计策略，通过多轮筛选以及结构优化，设计开发出小分子YB-3-17，其表现出优于mTOR抑制剂MLN0128的肿瘤抑制活性、选择性和安全性。该化合物验证了双靶点、双机制策略的可行性，为抗肿瘤药物开发提供了新的治疗思路。参考文献 Yongbo Liu, Xiuyun Sun, Qianlong Liu, Chi Han, Yu Rao. A Dual-Target and Dual-Mechanism Design Strategy by Combining Inhibition and Degradation Together. J Am Chem Soc. 2024 Dec 2. doi: 10.1021/jacs.4c11930 封面图来源：pixabay 《生物安全法案》再遇挫，药明系周一开盘大涨！ 2024-12-09 Acta Pharmacol Sin| 上海药物所评测AlphaFold3的GPCR-配体复合物预测表现能力显示实验结构的必要性 2024-12-08 里程碑！乙肝治愈率首次突破30%大关 2024-12-07 版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 点击，报名参加肝病会议!

免疫疗法细胞疗法

2023-04-18

·PRNewswire

Presage to Present at AACR 2023 - Core CIVO Technology Reveals Unexpected Effects of an Investigational Ubiquitination Inhibitor on Checkpoint Blockade

SEATTLE, April 17, 2023 /PRNewswire/ -- Presage Biosciences, a pioneer in translational oncology whose mission is understanding the complexity of drug response in the tumor microenvironment (TME), will present at the Immunology, TME Minisymposium at the American Association for Cancer Research (AACR) 2023 Annual Meeting. In an independent study, Presage's innovative multiplexed trackable microdosing platform (CIVO®) was used to introduce an investigational ubiquitin inhibitor (TAK-243) alone and in combination with anti-PD1. The resulting data demonstrated that TAK-243 has potential to increase anti-tumor immunogenicity and prime tumors for response to immune checkpoint inhibition. The Session (MS.IM01.03 – Immune Checkpoints at Tumor Beds, #3476) is titled "TAK-243 increases tumor immunogenicity enhancing systemic anti-tumor immune response and tumor regression in combination with immune checkpoint inhibition in a syngeneic model of lymphoma" and will be presented live on April 17, 2023 from 3:52pm-4:07pm EST. "We are excited to showcase these novel findings on the TME and how we have paired CIVO with sophisticated spatial profiling to translate preclinical findings to human disease" said Richard Klinghoffer, Presage's Chief Executive Officer. "We continue our work with fellow innovators in oncology to deliver key translational data early in the clinical development process." After AACR 2023, Presage Biosciences' CIVO technology will be further showcased at two events: The 4th Annual International Phase-0/Microdosing Stakeholder Meeting in Boston, MA on April 24th. Presage is featured speaker, panel moderator and sponsor at this year's event; Life Science Innovation Northwest (LSINW) in Seattle, WA on April 25. LSINW is the Pacific Northwest's largest annual life science conference. About CIVO Comparative In Vivo Oncology (CIVO) is Presage's patented platform that enables multiplexed intratumoral microdosing and generation of deep spatial biology insights. Presage's CIVO technology and analysis capabilities are unparalleled at providing insight into drug-exposed areas of the intact tumor microenvironment. Presage is pairing the use of CIVO with molecular profiling technologies in both preclinical and Phase 0 trials in order to inform and de-risk oncology drug development. About Presage Presage Biosciences is a translational oncology company dedicated to understanding the complexity of drug response in the tumor microenvironment. Presage partners with oncology-focused pharmaceutical companies through strategic alliances along with other innovators who are at the forefront of spatial biology and oncology drug development. Presage is privately held and based in Seattle. For more information, visit . Media Contact: Julie Rathbun Rathbun Communications (206) 769-9219 [email protected] SOURCE Presage Biosciences

AACR会议免疫疗法

100 项与 TAK-243 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15013

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
晚期癌症	临床1期	美国	National Cancer Institute	2025-03-24
晚期淋巴瘤	临床1期	美国	National Cancer Institute	2025-03-24
惰性非霍奇金淋巴瘤	临床1期	美国	National Cancer Institute	2025-03-24
转移性实体瘤	临床1期	美国	National Cancer Institute	2025-03-24
难治恶性实体肿瘤	临床1期	美国	National Cancer Institute	2025-03-24
复发性实体肿瘤	临床1期	美国	National Cancer Institute	2025-03-24
难治性贫血伴原始细胞过多	临床1期	美国	National Cancer Institute	2025-03-12
难治性贫血伴原始细胞过多	临床1期	加拿大	National Cancer Institute	2025-03-12
复发性骨髓增生异常综合征	临床1期	美国	National Cancer Institute	2025-03-12
复发性骨髓增生异常综合征	临床1期	加拿大	National Cancer Institute	2025-03-12

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临床结果

适应症

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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


NCT02045095 (CTgov)	临床1期	晚期恶性实体瘤	29	TAK-243 (Schedule A: TAK-243 1 mg)	鹹鑰鹹憲膚願鬱淵觸淵 = 糧願廠餘蓋鹽憲遞夢淵製構網淵夢衊鬱齋積鏇 (壓鏇製鏇遞遞鹽糧製齋, 夢簾壓鑰範鏇積膚餘遞 ~ 築鑰鹽襯遞餘範鹽遞膚) 更多	-	2019-03-14
				TAK-243 (Schedule A: TAK-243 2 mg)	鹹鑰鹹憲膚願鬱淵觸淵 = 艱製製構糧網窪廠襯製製構網淵夢衊鬱齋積鏇 (壓鏇製鏇遞遞鹽糧製齋, 餘鑰範憲憲遞構簾選鹽 ~ 糧糧壓網衊鑰積網顧鑰) 更多