Phase I/II Open Label Study Evaluating the Safety and Efficacy of Combining STAT3 Inhibition (TTI-101) With Anti-PD-1 Therapy (Pembrolizumab) in Patients With Recurrent or Metastatic (RM) Head and Neck Squamous Cell Carcinoma (HNSCC)

To review safety and efficacy of TTI-101 plus Pembrolizumab in patients the Recurrent and Metastatic head and Neck Squamous Cell Carcinoma.

开始日期2025-09-23

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

NCT05845307

/ Withdrawn早期临床1期IIT

Randomized Pre-surgical Window-of-Opportunity Trial of TTI-101 in Patients With Stage II-IV Resectable HPV-negative Squamous Cell Carcinoma of the Head and Neck

To learn if TTI-101 can reduce the growth of HPV-negative squamous cell carcinomas of the head and neck when given before standard of care surgery.

开始日期2025-06-20

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+2]

NCT06141031

/ Recruiting临床1期IIT

Phase I/IB Trial of Radiotherapy in Combination With TTI-101 in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma

The survival rate for patients with pancreatic cancer remains at a dismal 10% or less at 5 years, and although trials integrating stereotactic body radiation therapy (SBRT) alone have shown improvement in local control, initial invigoration of immune response, and relief of symptom burden, SBRT has not demonstrated any improvement in survival. Preclinical research has established that STAT3 inhibition given concurrently with SBRT and in the maintenance phase acts as a synergistic agent that enhances the pro-inflammatory effects of SBRT while reducing its undesired effects (including fibrosis and immunosuppression). This study exploits the window of opportunity post-chemotherapy to advance the hypothesis that the addition of STAT3 inhibition in combination with SBRT will be safe and will enhance 2-year progression-free survival.

开始日期2024-01-16

申办/合作机构

Washington University School of Medicine

[+2]

100 项与 C-188-9 相关的临床结果

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100 项与 C-188-9 相关的转化医学

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100 项与 C-188-9 相关的专利（医药）

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项与 C-188-9 相关的文献（医药）

2025-11-01·Molecular Oncology

Article

作者: Ana Azeredo ; Bernardo Orr ; Manuel R. Teixeira ; Paula Paulo ; Andreia Brandão ; Elsa Gomes Paiva

Prostate cancer (PCa) is the fifth leading cause of cancer‐related death. The lack of data linking genomic alterations to targeted treatment strategies has hindered progress in disease management. Genomic rearrangements involving the ETS transcription factors ERG or ETV1 are among the most frequent genetic alterations in PCa; however, their clinical utility remains elusive. Using PCa cells overexpressing ETV1 or ERG, representing early and advanced disease stages, we unveiled a positive feedback loop between ETV1 and EGFR, with STAT3 acting as a downstream effector of ETV1–EGFR signaling. Analysis of external datasets revealed that both EGFR and STAT3 are significantly upregulated in ETV1‐positive PCa, consistent with ChIP‐seq data identifying them as direct ETV1 targets. Accordingly, combined inhibition of EGFR and STAT3 using Erlotinib and TTI‐101, respectively, led to a significant reduction in 2D and 3D cell growth of early and advanced PCa cells overexpressing ETV1. Collectively, our findings highlight EGFR–STAT3 activation as a novel ETV1‐regulated oncogenic pathway, providing a rationale for repurposing EGFR inhibitors in combination with STAT3 inhibitors as a therapeutic strategy for the 8–10% of prostate carcinomas characterized by ETV1 rearrangements/overexpression.

2025-09-01·Advanced Science

ROS‐Responsive Hydrogel for Localized Delivery of Nampt and Stat3 Inhibitors Exhibits Synergistic Antitumor Effects in Colorectal Cancer Through Ferroptosis Induction and Immune Microenvironment Remodeling

Article

作者: Xuefeng Fang ; Ying Yuan ; Shanshan Weng ; Saimeng Shi ; Yinuo Tan ; Mengyuan Yang ; Ji Wang ; Yier Lu ; Mi Mi ; Lina Qi ; Cheng Guo ; Chenyang Ye ; Lu Wang ; Chao Chen ; Rui Bai

Abstract:

Targeting Nampt to modulate NAD + metabolism and exert antitumor effects has become a research hotspot in the field of cancer metabolism. But early clinical trials have only achieved modest results, primarily due to the need for improved efficacy and the occurrence of severe systemic adverse effects. Therefore, enhancing antitumor efficacy and reducing the adverse effects of Nampt inhibitors are urgent challenges. The research reveals that the Nampt inhibitor FK866 can induce ferroptosis in colorectal cancer cells via the NAD + /Stat3/Gpx4 signaling axis. Furthermore, the combination of FK866 and the Stat3 inhibitor C188‐9 demonstrates a strong synergistic antitumor effect. Importantly, a reactive oxygen species (ROS)‐responsive hydrogel that encapsulates FK866 and C188‐9 for in situ drug delivery, effectively reducing systemic side effects, is developed. Intriguingly, mass cytometry time‐of‐flight (CyTOF) analysis indicates that the combined treatment with FK866 and C188‐9 exerts antitumor effects by increasing the infiltration of CD8 + T cells and neutrophils into the tumor, as well as enhancing the expression of immune‐regulatory molecules, including IFN‐γ, IL‐10, and perforin. Thus, this localized treatment not only minimizes systemic adverse effects, but also markedly amplifies antitumor efficacy through the modulation of both tumor cells and the tumor immune microenvironment, representing a promising antitumor treatment strategy.

2025-08-01·NEUROCHEMICAL RESEARCH

JAK2/STAT3 Signaling Pathway Modulates Acute Methylmercury Toxicity in the Mouse Astrocyte C8-D1A Cell Line

Article

作者: Aschner, Michael ; Bowman, Aaron B ; Ferrer, Beatriz ; Santamaria, Abel ; Wong, Maximus ; Rocha, João Batista ; Ahmed, Aafia

Abstract:

Methylmercury (MeHg), an environmental pollutant, reaches the human body predominantly through contaminated fish consumption, potentially leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key early response to MeHg-induced oxidative injury, positioning it as a potential therapeutic target. However, recent studies suggest that Nrf2 activation alone may not be sufficient to mitigate MeHg toxicity, indicating the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) signaling pathway, known for its role in cell growth and survival, has emerged as a potential player in redox homeostasis. In this study, we investigated the role of STAT3 in acute (≤ 24 h) MeHg-induced neurotoxicity. MeHg exposure induced STAT3 expression in C8-D1A astrocytic cells. Our data demonstrated that pharmacological inhibition of STAT3 using AG490 or C188-9 exacerbated MeHg-induced cell death and compromised antioxidant responses. Furthermore, to fully characterize the role of STAT3 in oxidative stress, we used two different antioxidants, N-acetylcysteine (NAC) and Trolox. Conversely, reactive oxygen species (ROS)-scavenging antioxidants partially ameliorated STAT3 activation, suggesting that MeHg-induced STAT3 activation is mediated, at least in part, by mechanisms independent of ROS. Our findings suggest that STAT3 contributes to neuroprotection against MeHg exposure in astrocytes and is, at least in part, regulated by the increase in ROS levels within these cells.

项与 C-188-9 相关的新闻（医药）

2026-09-29

·精准药物

【JMC】一个强效 STAT3 抑制剂的发现

肿瘤药物筛选服务 2026.09.25 Online 近日，中国药科大学余文颖、来茂德、邓昭团队在期刊 Journal of Medicinal Chemistry 上发表了一篇题为《口袋条件自回归分子生成算法驱动强效 STAT3 抑制剂的发现及其结直肠癌治疗应用》（Pocket-Conditioned Autoregressive Molecular Generative Algorithm-Driven Discovery of a Potent STAT3 Inhibitor for Colorectal Cancer Treatment）的研究论文。该研究针对尚无抑制剂获批上市的明星靶点 STAT3，构建了融合蛋白口袋信息的自回归分子生成模型 PAMG，以已知 STAT3 抑制剂的磺酰胺与 1,4-萘醌优势片段为起点进行骨架装饰与虚拟筛选，经多轮成药性评估合成 32 个化合物，从中发现强效苗头化合物 11b。该化合物以亚微摩尔级活性（IC₅₀ = 0.64 μM）选择性抑制 STAT3 磷酸化与二聚化，效力约为 I 期临床药物 TTI-101 的 6 倍；在结直肠癌 HCT-116 移植瘤模型中，静脉与口服给药均展现出优于 TTI-101 和卡培他滨的肿瘤抑制效果（TGI 最高达 86%），且与卡培他滨联用产生协同抗瘤作用，同时表现出良好的体内安全性。该工作不仅为结直肠癌治疗提供了具有开发前景的 STAT3 抑制剂先导化合物，也示范了"AI 分子生成 + 药物化学"整合工作流在先导化合物发现中的实用价值。图文摘要 01 INTRODUCTION 研究背景转录因子 STAT3 是致癌信号传导的关键介导者，在多种癌症中频繁被激活，通过调控增殖、存活、血管生成和免疫逃逸相关基因促进肿瘤进展。STAT3 蛋白由 N 端结构域、螺旋-螺旋结构域、DNA 结合结构域、连接结构域、Src 同源 2（SH2）结构域和转录激活结构域组成，其中 SH2 结构域负责 STAT3 的磷酸化与二聚化，对其信号激活至关重要；STAT3 在上游激酶（如 JAK、EGFR、Src 和 ERK）作用下于 Tyr705 和 Ser727 位点磷酸化后发生二聚化并转位入核，促进致癌基因转录，且其过表达与磷酸化水平升高与癌症干性相关。鉴于上述作用，STAT3 抑制剂的开发备受关注，目前已报道的抑制剂包括天然产物、合成小分子、肽模拟物和 PROTAC 等多种类型，其中 TTI-101 和 BBI-608 最早进入实体瘤临床试验，STAT3/IRS1/2 双靶点抑制剂 NT291 也于 2025 年进入联合西妥昔单抗治疗头颈鳞状细胞癌的 II 期临床试验，但迄今尚无 STAT3 抑制剂获批临床应用。靶向 STAT3 的小分子开发长期面临挑战，主要原因是其 SH2 结构域配体结合表面平坦而浅，多数合成小分子仅表现出中等至较弱的结合亲和力，制约了后续临床开发；早期基于内源性磷酸肽结合物开发的肽类及肽模拟物抑制剂虽以膦酸基团模拟磷酸化酪氨酸侧链而获得高亲和力，却存在膜通透性差、细胞活性弱的问题，BP-PM6 的烷基膦酸酯前药策略仅部分改善了通透性和细胞效力；PROTAC 介导的 STAT3 降解虽在癌细胞中表现出较优的细胞活性，但长期蛋白水解降解可能导致正常组织靶点耗竭，存在扰乱生理功能的风险。近年来，深度学习为计算药物发现和从头小分子设计带来了变革，变分自编码器、生成对抗网络和 Transformer 等深度生成模型可从 ChEMBL、ZINC 等大规模化学数据库中学习分子潜在表示，实现靶点条件的化学空间探索，突破了传统高通量筛选和基于片段方法受限于化学空间与实验成本的瓶颈；然而，多数模型生成的化合物缺乏严格的实验验证，且往往不具备类药理化性质，难以真正产出加速现实药物开发的候选分子。 02 RESULTS AND DISCUSSION ①口袋条件自回归分子生成模型的开发与评估研究者在 BindingNet 高质量蛋白-配体复合物数据上训练了由 EGNN 口袋编码器（编码配体 10 Å 内残基）和 Transformer 自回归解码器组成的 PAMG 模型：配体按最小环系拆分并以超节点表示，以上下文骨架为输入、其余取代基为待召回目标，训练形式为局部结构补全任务。模型在留出测试集上表现良好：相似度截断 ≥0.7 时召回率超过 50%，生成物 86.0% 化学有效、85.7% 的合成可及性评分 ≤6，对接亲和力（−7.89 kcal/mol）优于参照分子（−7.32 kcal/mol），高亲和力比例 35.7%，展现出生成化学合理、结构多样且可合成分子的能力。与 LibINVENT、Pocket2Mol、DiffDec、DELETE、Pocket-StrMod、PocketXMol 等基线模型在 10,000 个分子上的对比显示：DELETE 和 DiffDec 对接亲和力最高但分别存在 log P 不利、合成难度大及 QED 低等缺陷，未施加口袋条件的 LibINVENT 和 Pocket2Mol 表现平淡，而 PAMG 在亲和力（−7.43 kcal/mol）与类药性间取得最佳平衡（QED 最高 0.53、SA 最低 3.2、log P 2.61）。消融实验证实口袋信息不可或缺：仅保留主链或完全去除口袋均导致亲和力、高亲和力率及类药性指标退化，并增加分子量与受体原子碰撞。虚拟筛选富集实验中，PAMG、DELETE 和 DiffDec 的命中化合物数（对接分数 < −8.5 kcal/mol）在 250–3000 分子筛选规模下均多于传统 R-基团枚举，其中 PAMG 全程优于 DiffDec、与 DELETE 相当，提示其有助于在有限计算预算下提高活性命中富集率，但因分析规模有限尚不能得出确定性结论。 ②基于 PAMG 模型的新型 STAT3 抑制剂设计与优化为获得 PAMG 模型生成所需的输入骨架，研究者分析了已知 STAT3 抑制剂的结构，发现磺酰胺和醌类是两个反复出现的共有子结构，遂通过结构融合策略将二者整合，设计了两个以磺酰胺并 1,4-萘醌为特征的主要骨架（I 和 II）作为分子生成的起点；分子对接显示，两个骨架均可嵌入 STAT3 SH2 结构域的 pY 口袋，并与 Arg609、Ser611、Gln612、Lys591 等关键残基形成氢键，而醌母核 α、β 位邻近的 pY+X 与 pY+1 子口袋尚有空缺，为取代基生成提供了空间。随后，PAMG 被用于在醌环 α、β 位生成可适配 pY+X 和 pY+1 口袋的取代基，为避免潜在位阻冲突，α、β 位取代基的重原子数分别限制在 ≤10 和 ≤3，共生成 127 个分子；经 Lipinski 规则、QED 和 SA 过滤排除化学不合理及合成不可及的分子后剩余 93 个，经分子对接排除低亲和力分子（Vina 分数 > −6.0 kcal/mol），再依据药物化学经验检视结合构象，聚焦那些能合理占据 pY、pY+1 和 pY+X 口袋的分子，最终获得 I-a、II-a、II-b 三个化合物簇，其共同结构特征为 α 位连有取代苯基、取代苄基或脂肪氨基等基团，β 位则由甲基或甲氨基占据；研究者从这三个簇中选出 32 个代表性化合物进行了合成，供后续生物学评价。 ③抗结直肠癌增殖活性的初步筛选与构效关系分析由于 STAT3 的过表达与磷酸化升高是结直肠癌进展的标志，且 Western blot 显示 HCT-116 细胞中 STAT3 Tyr705 磷酸化水平最高（HT29、RKO、SW620 等结直肠癌细胞亦高于正常结肠上皮细胞 NCM460），研究者采用 CCK-8 法在 HCT-116 细胞上评价新合成化合物的抗增殖活性。源自 I-a 类的 6a–6j（苄基间位衍生）中，6d 活性最强（IC₅₀ = 2.52 μM）；II-a 类衍生物 7a–7e（环化磺酰胺母核并连有脂肪胺取代基）整体活性优于 I-a，IC₅₀ 为 2.50–3.80 μM，提示环化刚性骨架在细胞效力方面更具优势。将 7a–7e 的甲基替换为甲氨基、并以大体积苯基替换脂肪胺后得到 9a–9o、11a 和 11b，其中无取代的 9a IC₅₀ 为 4.11 μM。构效关系分析表明：苯环上引入烷基（9b、9c，IC₅₀ 6.25 和 5.53 μM）降低活性；强吸电子基团三氟甲基和羧基（9f、9h）几乎完全消除抗结直肠癌活性（IC₅₀ > 10 μM）；卤素取代中氯、溴（9i、9j）使效力降低 2–3 倍，而 3-氟及 3,4,5-三氟取代（9k、9n，IC₅₀ 2.76 和 1.03 μM）则改善活性；给电子的甲氧基、异丙氧基（9d、9e、9o）使 IC₅₀ 降至 1–3 μM；吗啉、乙酰唑胺等大体积取代基（9l、9m）活性显著减弱。最终在苯环 3、4 位引入未取代氨基所得 11a 和 11b 活性最优，其中 3-氨基苯基的 11b（IC₅₀ = 0.64 μM）强于 4-氨基的 11a（0.98 μM），约为临床在研 STAT3 抑制剂 TTI-101 的 6 倍。进一步在 SW620、HT29、HL-60、THP-1、BxPC-3、PANC1 等多种 STAT3 信号活跃的肿瘤细胞中的测试显示，11b 在所有细胞系中活性最强，且对结直肠癌细胞的抑制强于其他肿瘤细胞，凸显其在结直肠癌治疗中的潜力。 ④11b 抑制 STAT3 的机制研究为阐明 11b 的抗增殖机制，研究者首先通过等温滴定量热法（ITC）和表面等离子体共振（SPR）测定了其与 STAT3 的结合亲和力，两种方法所得解离常数分别为 4.91 μM 和 4.67 μM，ITC 显示两者结合为放热反应，SPR 则表明该相互作用具有较快的结合速率与解离速率、驻留时间较短。细胞热位移实验（CETSA）证实 11b 在细胞水平靶向 STAT3：5 μM 的 11b 可显著增强 60–68 °C 范围内细胞 STAT3 蛋白的热稳定性，而无活性的对照类似物 9m 即使在 10 μM 下也无此效应；对 STAT 家族的选择性考察显示，11b 对 STAT1 和 STAT5 的蛋白热稳定性无显著影响。功能层面的证据进一步表明 11b 的抗增殖作用源于 STAT3 抑制而非一般性细胞毒性：在 HCT-116 和 HT29 细胞中敲低 STAT3 后，11b 的 IC₅₀ 升高 5–6 倍；在正常结肠黏膜上皮细胞 NCM460（其 STAT3 磷酸化水平低于 HCT-116 和 HT29）中，11b 的 IC₅₀ 约比这两种结直肠癌细胞高 5 倍。分子对接预测了 11b 与 STAT3 的结合模式：11b 嵌入 pY 口袋，其磺酰胺基团与 Arg609 侧链形成氢键，3-氨基苯基伸入侧口袋并与 Ile634 主链形成另一氢键以稳定结合，该非共价相互作用可能贡献了其相对类似物增强的效力；与 TTI-101 的对接对比显示，TTI-101 同样经磺酰胺结构与 Arg609 成键，但两个萘环的二面角接近 90°，侧环占据 pY+X 口袋而羟基朝向溶剂可及区，预测亲和力（−6.8 kcal/mol）略逊于 11b（−7.1 kcal/mol），后者因额外与 Ile634 形成氢键、且氨基取代苯基与甲氨基分别适配 pY+1 和 pY+X 口袋，对 SH2 结构域的占据更为充分。信号通路层面，Western blot 显示 11b 在 0.5–2 μM 浓度下剂量依赖性地抑制 HCT-116 和 HT29 细胞中 STAT3 Tyr705 的磷酸化，但对 STAT3 总表达量影响甚微；2 μM 时呈时间依赖性抑制，HCT-116 细胞中磷酸化在给药 6 小时后开始下降、24–48 小时几乎消失，HT29 细胞中 24 小时后仍维持抑制，而无活性的 9m 即使在 4 μM 下也无影响。选择性方面，2 μM 的 11b 对 STAT1、STAT5 的表达与磷酸化均无显著影响，对 STAT3 上游激酶 JAK2 和 ERK 的磷酸化也无明显作用，说明 STAT3 磷酸化的降低并非源于上游激酶活性的改变，上述结果共同确证 11b 是一种不与其他 STAT 亚型交叉反应的 STAT3 高选择性抑制剂。 ⑤化合物 11b 抑制结直肠癌细胞增殖与迁移并诱导其凋亡已知持续激活的 STAT3 信号通路与结直肠癌细胞的增殖、迁移增强及凋亡减少相关，因此研究者从多个层面考察了 11b 的体外抗结直肠癌活性。克隆形成实验显示，11b 以剂量依赖方式显著抑制 HCT-116 和 HT29 细胞的克隆形成能力，2 μM 处理几乎完全阻断克隆形成；由于球体形成能力对肿瘤细胞干性至关重要，进一步的球体形成实验表明 11b 能显著抑制结直肠癌细胞球体的形成并诱导球体解体，提示其可抑制肿瘤干细胞样细胞的自我更新与增殖。划痕愈合实验显示，11b 在 0.5–1 μM 浓度下即可显著抑制 HCT-116 细胞的迁移，凸显其抗转移活性。在分子机制层面，持续激活的 STAT3 可协同调控细胞周期与凋亡相关蛋白（包括细胞周期关键调控因子 cyclin D1、抗凋亡蛋白 Bcl-xL 及凋亡抑制蛋白家族成员 survivin）的表达；RT-qPCR 结果显示 11b 以浓度依赖方式显著降低 HCT-116 和 HT29 细胞中 cyclin D1、BCL2L1 和 survivin 的 mRNA 水平（无活性的 9m 对这三个基因均无显著影响），Western blot 进一步证实 11b 以浓度依赖方式抑制上述三种蛋白的表达，并在 0–48 小时内呈时间依赖性降低其蛋白水平，说明 11b 抑制了 STAT3 依赖的转录活性。凋亡实验方面，Hoechst 染色显示 0.5–2 μM 的 11b 处理 48 小时后细胞出现核固缩、碎裂等典型凋亡形态；流式细胞术检测证实 11b 在 0.5–2 μM 浓度下可诱导 HCT-116 细胞凋亡；Western blot 还观察到 11b 处理后 HCT-116 和 HT29 细胞中裂解型 PARP（cleaved PARP）水平升高，进一步佐证其凋亡诱导作用。综上，11b 通过抑制增殖与迁移并诱导凋亡，在体外展现出强效的抗结直肠癌活性。 ⑥11b 在 SD 大鼠中的药代动力学研究基于体外实验的良好结果，研究者在 Sprague-Dawley（SD）大鼠中评价了 11b 单剂量静脉注射（2 mg/kg）和口服给药（50 mg/kg）后的药代动力学特征。静脉注射后，11b 的平均清除率为 1.31 ± 0.12 L/h/kg，平均半衰期（t₁/₂）为 5.18 ± 2.41 小时，提示其代谢稳定性较好，0–t 时间曲线下面积（AUC₀₋ₜ）为 1488.25 ± 160.16 h·μg/L，分布容积为 9.9 ± 5.22 L/kg。口服给药后，11b 的口服生物利用度（F）为 14.72%，AUC₀₋ₜ 达 5641.18 ± 738.35 h·μg/L，达峰时间约为 0.81 ± 0.89 小时，表现出优化的血浆暴露水平和口服生物利用度。上述药代动力学结果支持将 11b 作为新型抗结直肠癌候选药物开展进一步的体内评价。 ⑦11b 在 HCT-116 小鼠异种移植瘤模型中的抗结直肠癌活性研究者首先在 HCT-116 小鼠异种移植瘤模型中通过静脉给药考察 11b 的体内抗结直肠癌活性，以 TTI-101 为阳性对照：当肿瘤体积达到约 80 mm³ 时将小鼠随机分为 11b 低剂量组（10 mg/kg）、高剂量组（20 mg/kg）、TTI-101 组（20 mg/kg）和生理盐水对照组（每组 n = 8），每日尾静脉注射一次、连续 14 天。结果显示，11b 以剂量依赖方式显著抑制肿瘤生长，低、高剂量组的肿瘤生长抑制率（TGI）分别为 68% 和 81%，均优于 TTI-101（60%）；整个治疗期间小鼠体重无显著变化，主要器官的 HE 染色未见可检测的组织病理学改变，提示静脉注射 11b 的安全性良好。随后，研究者以结直肠癌化疗中广泛应用的卡培他滨为阳性对照，考察了口服给药的抗肿瘤效果：11b（150 mg/kg）与卡培他滨（150 mg/kg）每日灌胃一次、连续 21 天，11b 组的 TGI 达 86%，强于等剂量卡培他滨的 69%，且给药期间小鼠体重持续增加，提示 150 mg/kg 剂量下 11b 毒性轻微，HE 染色亦未见各组器官的组织病理学异常。鉴于已有研究表明 STAT3 过表达导致结直肠癌化疗耐药、抑制 STAT3 可与化疗协同抑瘤，研究者进一步评估了 11b 与化疗的联用效果：体外 CCK-8 实验显示 11b 与 5-FU（卡培他滨的活性形式）以 1:1 摩尔比处理时以协同方式抑制 HCT-116 增殖（联合指数 CI < 1.0）；将 11b 浓度固定为其 IC₅₀ 值（0.64 μM）时，5-FU（1.25–5 μM）与 11b 联用的 CI 为 0.62–0.68，呈协同效应。体内实验中，基于表观分布容积和生物利用度将口服剂量设为 50 mg/kg，与低剂量卡培他滨（100 mg/kg）联用 21 天后，联合用药组的肿瘤抑制（TGI = 84%）强于 11b 单药（66%）或卡培他滨单药（47%），也优于 150 mg/kg 卡培他滨单药（69%）；联合组的 TGI 略高于按 Bliss 独立模型计算的两种单药 TGI 简单加和，提示两者可能以协同方式抑制结直肠癌生长，且联合组小鼠体重仅在第 1–9 天略有下降、随后持续回升，主要器官 HE 染色未见异常，证实联合用药安全。肿瘤组织的 Western blot 显示，11b 单药或联合用药均显著降低 STAT3 Tyr705 磷酸化水平，印证了体内对 STAT3 信号的抑制；有趣的是，卡培他滨处理组肿瘤组织中 STAT3 及其磷酸化水平也下降，研究者推测这可能与 HCT-116 细胞对 STAT3 信号通路的生存依赖性有关。综上，静脉和口服给药的 11b 在结直肠癌治疗中均表现出优于临床在研 STAT3 抑制剂及卡培他滨的抑瘤效力与良好安全性，无论作为单药还是与卡培他滨联用均显示出应用前景。总结与展望尽管 STAT3 在肿瘤进展与免疫调控中的作用明确，迄今尚无 STAT3 抑制剂获批上市，其难点在于 SH2 结构域缺乏理想的配体结合口袋，使兼具高亲和力与强细胞活性的小分子设计颇为困难：含磷酸类似物的肽模拟物亲和力高却膜通透性差、细胞活性弱，因而亟需兼顾亲和力与类药性质的小分子 STAT3 抑制剂。本研究开发的 PAMG 模型整合 EGNN 编码的三维口袋约束与自回归生成器，经多指标评估虽对接亲和力略逊于 DELETE 和 DiffDec，但在合成可及性与类药性上更优（QED 0.53、log P 2.61），更契合真实药化研究对可开发性的要求；消融实验证实模型性能依赖完整口袋信息，初步筛选结果亦提示其比传统 R-基团枚举更易产出高亲和力命中化合物。基于此，研究者以磺酰胺和 1,4-萘醌片段设计骨架，经生成、对接与人工检视合成 32 个化合物，发现强效选择性抑制剂 11b，其抗结直肠癌活性优于 TTI-101，中等口服生物利用度（14%）；体内静脉给药 20 mg/kg 的 TGI 达 81%（优于 TTI-101 的 60%），口服 150 mg/kg 的 TGI 达 86%，降剂量与卡培他滨联用 TGI 为 84%（优于 150 mg/kg 卡培他滨单药的 69%）且无明显毒性，显示对抗化疗耐药的潜在价值。作者同时保持审慎：输入母核由药化知识设计、生成分子规模较小且经人工检视，削弱了判断 PAMG 真实贡献的能力，11b 的发现可能是多环节共同作用的结果，模型在多取代位点及大体积取代基任务中的价值尚待验证；模型亦未考虑诱导契合与水介导相互作用，未来需引入动态口袋构象并开展大规模实验验证与公开基准测试。11b 自身的局限在于口服生物利用度仅 14%、需高剂量给药，醌类母核可能带来氧化还原干扰与毒性、需长期安全性研究，其治疗耐药结直肠癌的潜力尚需在耐药细胞系和 PDX 模型中验证，体内协同效应轻微、给药组合待优化。总体而言，PAMG 在生成高亲和力、可合成、类药性分子方面优势突出，11b 是强效的新型 STAT3 抑制剂，本工作是 AI 分子生成与药物化学结合的成功案例，11b 值得进一步结构优化与临床前研究。文献详细全面信息请跳转原文阅读： https://doi.org/10.1021/acs.jmedchem.6c01573 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↓

上市批准临床1期临床结果蛋白降解靶向嵌合体

2026-09-29

·BioSpace

New Preclinical Data Further Support Potential for Tvardi’s STAT3 Inhibitors in Ulcerative Colitis (UC)

In a preclinical chronic colitis model, Tvardi’s oral small molecule accumulated in the colon at approximately 8-fold higher concentrations than in plasma, at pharmacologically relevant levels, and modulated STAT3-driven disease biology Collective findings now span multiple preclinical models of UC, further supporting the scientific rationale for advancing TTI-109, Tvardi’s next-generation STAT3 inhibitor, in UC HOUSTON, Sept. 24, 2026 (GLOBE NEWSWIRE) -- Tvardi Therapeutics, Inc. (“Tvardi” or the “Company”) (NASDAQ: TVRD), a clinical-stage biopharmaceutical company focused on the development of novel, oral small molecule therapies targeting STAT3 to treat inflammatory and proliferative diseases, today announced the publication of preclinical data evaluating Tvardi’s STAT3 inhibitor in the International Journal of Molecular Sciences . The publication provides additional evidence supporting further investigation of STAT3 inhibition as a potential therapeutic approach to treating inflammatory bowel diseases, including ulcerative colitis (UC). The publication, titled “Colitis-Associated Colorectal Cancer—STAT3 Inhibition as a Preventive Strategy,” evaluated Tvardi’s first-generation oral STAT3 inhibitor, TTI-101, in an azoxymethane (AOM)-dextran sodium sulfate (DSS) mouse model, designed to replicate the human progression from chronic colitis to colorectal cancer (CRC). Patients with UC are estimated to have a 20- to 30-fold higher risk of CRC than the general population. In this model, the orally administered STAT3 inhibitor reached pharmacologically relevant concentrations in the colon, normalized STAT3-regulated colonic gene expression and modulated proliferative programs associated with colitis-driven disease progression, preventing the development of colon polyps and adenocarcinomas. The chronic AOM-DSS prevention model is the fourth preclinical model of colitis in which Tvardi’s STAT3 inhibitors have shown biological activity. Previously, Tvardi’s oral small molecules normalized the UC hallmarks of immune dysregulation, inflammation and proliferation across three acute models representing distinct immune axes: DSS (innate/Th17), trinitrobenzene sulfonic acid (TNBS; adaptive Th1) and oxazolone (OXA; adaptive Th2/NKT). “UC is a multifactorial disease shaped by three interconnected processes: immune dysregulation, inflammation and proliferation, each of which is regulated by STAT3. Current advanced therapies are designed primarily to target inflammation,” said Imran Alibhai, Ph.D., Chief Executive Officer of Tvardi Therapeutics. “Even patients who reach endoscopic remission are not disease-free: 98% retain lesions composed of B- and T-cell aggregates, inflammatory infiltrates and distorted crypts associated with the chronic disease characteristics of UC. In this preclinical model, oral STAT3 inhibition achieved high exposure in the colon and normalized gene expression spanning unique STAT3-regulated programs associated with relapse and progression. We believe these findings demonstrate the potential of STAT3 inhibition in modulating multiple aspects of the underlying disease biology with a pro for gastrointestinal indications requiring high mucosal drug exposure.” Findings relevant to UC include: High colon exposure: TTI-101 achieved approximately 8-fold higher drug levels in the colon than in plasma, indicating accumulation in the target organ, at pharmacologically relevant levels for inhibition of STAT3-dependent proliferation. Broad effects on disease-associated gene expression: TTI-101 reversed many disease-induced changes in colon gene expression, including genes associated with colorectal cancer and STAT3 signaling. The normalized genes span the principal axes of UC biology: regulators of cellular immune responses, including recognized IBD/UC susceptibility genes, components of the humoral immune response, inflammatory and acute-phase mediators and epithelial-barrier and proliferative genes. Normalizing gene expression across these interacting programs, rather than blocking a single mediator, supports the potential of STAT3 inhibition to interrupt the chronic disease process. TTI-101 prevented tumors from forming: TTI-101 prevented adenocarcinoma formation entirely (p≤0.05), while pY-STAT3 (activated STAT3) was found to be elevated in the tumors that developed in vehicle-treated animals. TTI-101 reached levels more than 20 times the STAT3 IC 50 (the concentration needed to block STAT3-driven growth) in the colon. These prevention results build on earlier work in the chronic AOM-DSS treatment model 1 , in which TTI-101, given as treatment after colitis was established, achieved high drug exposure in the colon and statistically significantly reduced tumor formation. Addressing the chronic nature of UC: UC is a chronic, relapsing disease driven by three linked, STAT3-regulated processes: immune dysregulation, inflammation and proliferation. Current advanced therapies are directed primarily at inflammation, and placebo-adjusted clinical remission rates remain below 30%. Genetic and pharmacologic studies have implicated activated STAT3 in the severity of colitis; pY-STAT3 inhibition has shown activity across both short- and long-term treatment settings. In three acute models representing distinct immune axes of UC, TTI-101/TTI-109 statistically significantly reduced immune dysregulation, diarrhea, colonic inflammation, colon shortening and pY-STAT3 in the colon. In the longer-term AOM-DSS model, TTI-101 demonstrated activity after colitis was established. In the present study, after ten weeks of continuous dosing in mouse models, TTI-101 sustained normalization of the colon transcriptome and prevented the development of colon adenocarcinomas, a long-term consequence of chronic colitis. Across Tvardi’s clinical data, STAT3 inhibition modulated the same three-part signature: reduced key immune cell populations in healthy volunteers, reduced IL-6, a central pro-inflammatory cytokine that signals through STAT3, and reduced fibrosis score in patients with idiopathic pulmonary fibrosis. Taken together, these findings suggest the potential for STAT3 inhibition to act on the underlying biology leading to and driving the chronic nature of UC. “Building on our experience with TTI-101, we developed TTI-109 as a next-generation prodrug designed to preserve TTI-101’s STAT3-targeting mechanism while improving drug delivery and tolerability. Our recently completed Phase 1 healthy volunteer study of TTI-109 demonstrated predictable pharmacokinetics, favorable GI tolerability and modulation of UC-relevant immune cell populations, which we believe further supports our development in UC,” Dr. Alibhai concluded. The publication can be found here . Robinson P, et al. STAT3 Inhibition to Treat Ulcerative Colitis-Associated Colorectal Cancer. Int J Mol Sci . 2025;26(21):10808. About Tvardi Therapeutics Tvardi is a clinical-stage biopharmaceutical company focused on the development of novel, oral small molecule therapies targeting STAT3 to treat inflammatory and proliferative diseases with significant unmet need. STAT3 is a central mediator across critical signaling pathways that drive uncontrolled proliferation, survival and immune dysregulation. STAT3 is also positioned at the intersection of many signaling pathways integral to the survival and immune evasion of cancer cells. The Company has completed a Phase 1 healthy volunteer study of TTI-109 and plans to initiate clinical trials of TTI-109 in gastrointestinal (GI) diseases pending IND clearance and the availability of additional funding. The Company is also conducting a Phase 1b/2 clinical trial of TTI-101 in hepatocellular carcinoma ( NCT05440708 ). To learn more, please visit tvarditherapeutics.com or follow us on LinkedIn and X (Twitter) . Contacts: For Tvardi: Tvardi Investor Relations ir@tvardi.com PJ Kelleher LifeSci Advisors 617-430-7579 pkelleher@lifesciadvisors.com Cautionary Statement Regarding Forward-looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Examples of these forward-looking statements include statements concerning the anticipated benefits of Tvardi’s product candidates, including TTI-101 and TTI-109 in UC and of the Company’s STAT3 inhibitors, including in modulating underlying UC disease biology; the potential benefits of TTI-109 as compared to TTI-101, including improved delivery and tolerability; its ongoing and planned clinical trials; the results from preclinical models of UC supporting the advancement of TTI-101 and TTI-109 into future clinical trials; the Company’s plans to develop TTI-109 in UC; and other statements regarding management’s intentions, plans, beliefs, expectations or forecasts for the future, and, therefore, you are cautioned not to place undue reliance on them. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are subject to a number of risks, including, among other things: the uncertainties associated with Tvardi’s product candidates, as well as risks associated with the clinical development and regulatory approval of product candidates, including potential delays in the completion of clinical trials or safety or other complications related to its product candidates; the ability to replicate the positive results from preclinical studies or early clinical trials in future clinical trials; the ability to obtain IND clearance for TTI-109 in GI therapeutic areas on the timelines expected or at all; the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all; the significant net losses Tvardi has incurred since inception; Tvardi’s ability to initiate and complete ongoing and planned preclinical studies and clinical trials and advance its product candidates through clinical development; the timing of the availability of data from Tvardi’s clinical trials; the outcome of preclinical testing and clinical trials of Tvardi’s product candidates, including the ability of those trials to satisfy relevant governmental or regulatory requirements; Tvardi’s plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of Tvardi’s product candidates; the estimated patient populations and total addressable markets for the indications in which Tvardi seeks to develop its product candidates; Tvardi’s anticipated cash runway; Tvardi’s ability to attract, hire, and retain skilled executive officers and employees; Tvardi’s ability to protect its intellectual property and proprietary technologies; Tvardi’s reliance on third parties, contract manufacturers and contract research organizations; the possibility that Tvardi may be adversely affected by other economic, business or competitive factors; risks associated with changes in applicable laws or regulations; those factors discussed in Tvardi’s filings with the Securities and Exchange Commission, including the “Risk Factors” section of the Annual Report on Form 10-K for the year ended December 31, 2025, and Tvardi’s other documents subsequently filed with or furnished to the SEC, all of which are available on the SEC’s website at All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

临床1期临床结果临床申请

2026-09-01

·奇点网

《癌症通讯》：中国科学家发现肝癌免疫逃逸新机制，STAT3抑制剂或可用于增强免疫治疗效果！

*仅供医学专业人士阅读参考肝细胞癌（HCC）是全球范围内高致死性的恶性肿瘤之一。尽管以PD-1/PD-L1抑制剂为代表的免疫疗法为不可切除或晚期肝癌患者带来了生存曙光，但免疫耐药依然是临床上面临的巨大挑战。自然杀伤（NK）细胞作为人体固有免疫的第一道防线，在抗肿瘤免疫中发挥着关键作用。然而，在肝癌微环境中，NK细胞往往处于严重的功能抑制状态，表现为浸润减少和杀伤活性丧失，其背后的分子机制长期未能被完全阐明。今日，《癌症通讯》杂志发表了来自复旦大学附属中山医院和上海交通大学医学院附属瑞金医院科研团队的论文，该研究首次揭示了RNA甲基转移酶NSUN2通过介导糖酵解关键酶mRNA的m5C修饰促进乳酸积累，进而通过组蛋白乳酸化修饰（H3K18la）表观激活PD-L1表达，最终抑制NK细胞杀伤力、驱动肝癌免疫逃逸的全新机制。研究者对人肝癌细胞进行了CRISPR/Cas9文库筛选，鉴定到86个敲除后能显著增强肝癌细胞对NK细胞敏感性的靶基因。交叉对比TCGA数据库中与NK细胞浸润负相关的基因及19种癌症高表达基因后，研究者锁定了NSUN2，这是一种RNA m5C甲基转移酶。实验结果显示，敲除NSUN2能显著增强NK细胞对肝癌细胞的细胞毒性，促进NK细胞形成更丰富的免疫突触和膜表面突起，并显著提升NK细胞释放IFN-γ和颗粒酶B（GZMB）的能力。研究者通过甲基化RNA免疫共沉淀测序和转录组测序发现，NSUN2直接结合并介导糖酵解通路中三个核心酶的mRNA的m5C修饰，包括烯醇化酶1（ENO1）、丙酮酸激酶M1/2（PKM）和乳酸脱氢酶A（LDHA）。这一修饰能够显著延长三种mRNA的半衰期。NSUN2的高表达导致肝癌细胞糖酵解异常活跃，细胞外酸化率（ECAR）和乳酸（Lactate）产量大幅增加。当敲除NSUN2后，代谢发生重构，糖酵解受阻，乳酸产量显著下降。乳酸是组蛋白H3K18la修饰的重要原材料，这一乳酸化修饰显著提高了癌细胞PD-L1/CD274启动子区域染色质的可及性，使其更加开放，并招募STAT3结合至启动子的两个特定位点，从而启动PD-L1的转录与高表达，进而抑制NK细胞杀伤。鉴于STAT3在PD-L1表观激活中的关键桥梁作用，研究团队在原位肝癌和自发性肝癌小鼠中，联合使用了STAT3小分子抑制剂（TTI-101）与抗PD-L1抗体，二者表现出显著的协同效应，小鼠肝脏肿瘤负荷降低，生存期大幅度延长。对中山医院收治肝癌患者组织样本和TCGA队列的分析也发现，肝癌组织中存在NSUN2的高表达，且与患者的生存期缩短、免疫治疗耐药显著相关。免疫治疗非响应者肿瘤组织中NSUN2、H3K18la及PD-L1呈高共表达，而NK细胞浸润显著减少。PD-1/PD-L1通路在T细胞中的研究较多，本研究也讨论了NSUN2/PD-L1轴是否影响CD8阳性T细胞的功能。但清除CD8阳性T细胞并不影响敲除NSUN2带来的治疗获益，说明这一通路主要是由NK细胞驱动的。这也可能受到了研究者使用的低免疫原性/高依赖NK细胞的Hepa1-6肝癌模型影响。研究发现了NSUN2/乳酸/H3K18la/STAT3/PD-L1/NK细胞这一全新的免疫治疗耐药通路，或可成为提升肝癌免疫治疗敏感性，攻克耐药的下一个突破口。欢迎大家关注我们在小宇宙上的播客栏目——药研片语，欢迎大家前去收听并与我们交流~参考资料：[1]Mao, Shengwei, et al. "Metabolic Reprogramming of NSUN2-Mediated m5C Modification Promotes the Progression of Hepatocellular Carcinoma by Restricting Natural Killer Cell-Mediated Cytotoxicity." Cancer Communications, vol. 46, 2026, p. 0043, https://doi.org/10.34133/cancomm.0043.本文作者丨代丝雨

100 项与 C-188-9 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
复发性头颈部鳞状细胞癌	临床2期	-	The University of Texas MD Anderson Cancer Center	2025-09-23
特发性肺纤维化	临床2期	美国	Tvardi Therapeutics, Inc.	2023-05-15
局部晚期肝细胞癌	临床2期	美国	Tvardi Therapeutics, Inc.	2023-03-23
晚期胰腺导管腺癌	临床1期	美国	Tvardi Therapeutics, Inc.	2024-01-16
晚期乳腺癌	临床1期	美国	Tvardi Therapeutics, Inc.	2023-01-09
HR阳性/HER2阴性乳腺癌	临床1期	美国	Tvardi Therapeutics, Inc.	2023-01-09
局部晚期乳腺癌	临床1期	美国	Tvardi Therapeutics, Inc.	2023-01-09
PIK3CA突变/HR阳性/HER2阴性乳腺癌	临床1期	美国	Tvardi Therapeutics, Inc.	2023-01-09
乳腺癌	临床1期	美国	The University of Texas MD Anderson Cancer Center	2017-11-15
结直肠癌	临床1期	美国	Tvardi Therapeutics, Inc.	2017-11-15

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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


NCT05384119 (CTgov)	临床1期	PIK3CA突变/HR阳性/HER2阴性乳腺癌 \| 乳腺癌 \| 局部晚期乳腺癌 ... 更多	6	TTI-101+palbociclib (Phase 1b: Dose Level 1)	齋餘鑰遞醖顧鑰鏇夢餘 = 憲顧積膚繭觸鹹構網醖範糧願鹽顧夢鏇鹽鑰鬱 (製願襯衊遞衊構餘鏇構, 觸齋願糧衊夢簾膚獵夢 ~ 選鬱鏇糧顧鬱蓋襯餘蓋) 更多	-	2026-09-24
				TTI-101+palbociclib (Phase 1b: Dose Level 2)	齋餘鑰遞醖顧鑰鏇夢餘 = 遞憲願鹽膚膚廠艱蓋壓範糧願鹽顧夢鏇鹽鑰鬱 (製願襯衊遞衊構餘鏇構, 鹽鬱壓遞繭淵廠餘構餘 ~ 積簾窪鹹願糧積遞憲選) 更多
NCT05671835 (REVERT-IPF, Company_Website) 人工标引	临床2期	特发性肺纤维化	88	TTI-101 400mg per day	廠夢齋蓋願壓積築顧廠(襯鹽壓膚壓膚選膚遞觸) = 壓網範鏇蓋艱築廠蓋壓蓋築顧鬱膚鹽積齋憲膚 (齋積廠鏇糧鹽鏇淵齋鹽 ) 更多	不佳	2025-10-13
				TTI-101 800mg per day	廠夢齋蓋願壓積築顧廠(襯鹽壓膚壓膚選膚遞觸) = 膚齋鏇積餘衊蓋膚製憲蓋築顧鬱膚鹽積齋憲膚 (齋積廠鏇糧鹽鏇淵齋鹽 ) 更多
NCT03195699 (Pubmed) 人工标引	临床1期	晚期恶性实体瘤	64	TTI-101 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day	醖構顧淵選膚築簾壓夢(齋鏇構簾夢齋選廠積鑰) = 餘糧醖鹹獵壓壓淵壓淵鬱廠遞選簾餘齋鑰齋製 (鏇襯衊築壓壓積憲選製 ) 更多	积极	2025-03-17
NCT05440708 (Phase 1b/2 study, ASCO_GI2024)	临床1/2期	晚期肝细胞癌 STAT3 activation	-	TTI-101 (monotherapy)	網願築製鏇淵齋夢鏇構(網膚鹹齋範積鑰齋糧壓) = 積憲襯鏇膚繭範淵願觸廠積鹽築餘鬱網積繭積 (願顧鏇顧鑰願鏇鑰糧鬱 ) 更多	积极	2024-01-18
NCT03195699 (ASCO 12023 \| ASCO 22023) 人工标引	临床1期	晚期恶性实体瘤	39	TTI-101	醖廠遞膚鏇壓鏇繭繭選(範顧築夢餘積繭淵壓膚) = No dose limiting toxicities (DLTs), or fatal treatment-related adverse events (TRAEs) were observed. 廠積範糧鹽觸夢範窪積 (衊遞壓獵醖齋餘廠鬱遞 ) 更多	积极	2023-05-31
				TTI-101 (hepatocellular carcinoma)