An Open-Label, Randomized, Phase 2, Umbrella Study to Investigate the Biological Rational of Various Neoadjuvant Therapies for Participants With Muscle-Invasive Urothelial Carcinoma of the Bladder Who Are Cisplatin-Ineligible or Refuse Cisplatin Therapy and Undergoing Radical Cystectomy

This is a multicenter, open-label, randomized, Phase 2 umbrella study of various neoadjuvant treatment combinations in participants who have muscle-invasive urothelial carcinoma of the bladder and are cisplatin-ineligible or refusing cisplatin therapy and awaiting radical cystectomy.

开始日期2022-01-14

申办/合作机构

Incyte Corp.

NCT04463771

/ Active, not recruiting临床2期

An Umbrella Study of INCMGA00012 Alone and in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-Based Chemotherapy (POD1UM-204)

This is a multicenter, open-label, nonrandomized, Phase 2 umbrella study of retifanlimab in participants who have advanced or metastatic endometrial cancer that has progressed on or after platinum-based chemotherapy. retifanlimab will be administered as monotherapy or in combination with other immunotherapy or targeted agents.

开始日期2021-01-26

申办/合作机构

Incyte Corp.

[+2]

NCT04231864

/ Withdrawn临床2期IIT

A Multi-Center, Phase II, Open Label, Single-Arm Trial of Durvalumab and Epacadostat in Patients With Unresectable, Recurrent, and Metastatic EBV+ NPC

This phase II trial studies how well durvalumab and epacadostat work in treating patients with Epstein-Barr virus positive nasopharyngeal cancer that cannot be removed by surgery (unresectable), has come back (recurrent), or has spread to other places in the body (metastatic). Epacadostat blocks the enzyme, IDO1, from working. Blocking this enzyme may allow for a stronger immune response against cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving durvalumab and epacadostat may work better in treating patients with nasopharyngeal cancer compared to durvalumab alone.

开始日期2020-12-01

申办/合作机构

The University of California, San Francisco

[+2]

100 项与艾卡哚司他相关的临床结果

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100 项与艾卡哚司他相关的转化医学

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100 项与艾卡哚司他相关的专利（医药）

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213

项与艾卡哚司他相关的文献（医药）

2025-09-02·Journal of biomolecular structure & dynamics

Discovery of novel IDO1/TDO2 dual inhibitors: a consensus Virtual screening approach with molecular dynamics simulations, and binding free energy analysis

Article

作者: Sari, Suat ; Hanif, Naufa

The pursuit of effective cancer immunotherapy drugs remains challenging, with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) allowing cancer cells to evade immune attacks. While several IDO1 inhibitors have undergone clinical testing, only three dual IDO1/TDO2 inhibitors have reached human trials. Hence, this study focuses on identifying novel IDO1/TDO2 dual inhibitors through consensus structure-based virtual screening (SBVS). ZINC15 natural products library was refined based on molecular descriptors, and the selected compounds were docked to the holo form IDO1 and TDO2 using two different software programs and ranked according to their consensus docking scores. The top-scoring compounds underwent in silico evaluations for pharmacokinetics, toxicity, CYP3A4 affinity, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations. Five compounds (ZINC00000079405/10, ZINC00004028612/11, ZINC00013380497/12, ZINC00014613023/13, and ZINC00103579819/14) were identified as potential IDO1/TDO2 dual inhibitors due to their high consensus docking scores, key residue interactions with the enzymes, favorable pharmacokinetics, and avoidance of CYP3A4 binding. MD simulations of the top three hits with IDO1 indicated conformational changes and compactness, while MM-GBSA analysis revealed strong binding free energy for compounds 10 (ΔG: -20.13 kcal/mol) and 11 (ΔG: -16.22 kcal/mol). These virtual hits signify a promising initial step in identifying candidates as supplementary therapeutics to immune checkpoint inhibitors in cancer treatment. Their potential to deliver potent dual inhibition of IDO1/TDO2, along with safety and favorable pharmacokinetics, makes them compelling. Validation through in vitro and in vivo assays should be conducted to confirm their activity, selectivity, and preclinical potential as holo IDO1/TDO2 dual inhibitors.

2025-08-19·Journal of the American Heart Association

IDO‐1 Promotes Pulmonary Vascular Remodeling Via Kynurenine Pathway in Pulmonary Arterial Hypertension

Article

作者: Wang, Sihao ; Yan, Yi ; Tian, Siyu ; Olschewski, Horst ; Nagy, Bence M ; Fu, Yahong ; Deng, Lin ; Tran-Lundmark, Karin ; Fu, Lijun ; Wang, Danan ; Li, Xiaoxuan ; van den Bosch, Thierry P P ; Boomars, Karin A ; Phan, Carole ; Guignabert, Christophe ; Merkus, Daphne ; Tu, Ly ; Cai, Zongye

Background:

Activation of the plasma kynurenine pathway (KP) may contribute to the progression of pulmonary arterial hypertension (PAH). We investigated the functional role and molecular mechanisms of KP activation in PAH.

Methods:

KP activity was measured in the lungs and plasma of humans and rodents with pulmonary hypertension (PH). KP activity was modulated in lung microvascular endothelial cells in vitro, and through daily oral administration of epacadostat, an inhibitor of IDO‐1 (indoleamine 2,3‐dioxygenase), the rate‐limiting enzyme of the KP, in rats with monocrotaline‐induced PH.

Results:

IDO‐1 expression was increased in peripheral blood mononuclear cells but not in lung tissue of patients with PAH and in rats with monocrotaline‐induced PH. Epacadostat prevented KP activation and the development of monocrotaline‐induced PH, significantly reduced right ventricular systolic pressure (58±9 versus 42±4 and 46±6 mm Hg for placebo versus epacadostat 50 and 100 mg/kg, respectively, P <0.001), pulmonary arterial remodeling (wall thickness, 64±3 versus 58±3 and 58±3%, P <0.001), perivascular inflammation, and right ventricular remodeling (Fulton index, 0.49±0.05 versus 0.36±0.06 and 0.39±0.04, P <0.001). IDO‐1 overexpression contributed to KP activation and de novo nicotinamide adenine dinucleotide + synthesis, increased mitochondrial membrane potential, and endothelial cell proliferation. Inhibition of IDO‐1 using siRNA or epacadostat reversed these effects and inhibited the inflammatory response.

Conclusions:

Increased IDO‐1 expression in peripheral blood mononuclear cells may drive KP activation and promote pulmonary vascular remodeling in PAH. Epacadostat prevents the development of monocrotaline‐induced PH. These findings suggest a novel approach for the treatment of PAH.

2025-08-01·JOURNAL OF CONTROLLED RELEASE

A TCR nanovesicle antibody for redirecting T cells and reversing immunosuppression as a tumor immunotherapy strategy

Article

作者: Tang, Yu ; Li, Chunli ; Qi, Hongbo ; Wang, Bozhi ; Li, Luo ; Jin, Aishun ; Zhang, Liang ; Li, Qian

T-cell receptor T-cell engagers (TCR-TCE) are soluble bispecific proteins composed of TCR and anti-CD3 antibodies, which can effectively redirect tumor-infiltrating T cells to kill tumor cells. However, TCR-TCE development and clinical application are significantly hindered by the instability of natural TCRs and immunosuppressive tumor microenvironment, underscoring the urgent need for alternative engineering strategies. Here, we describe a strategy that utilizes artificial cell membrane nanoparticle technology to generate a TCR nanovesicle antibody (TPC NV), which presents tumor-specific TCR, anti-CD3, and PD-1 antibodies on its membrane, representing a novel TCR-TCE with therapeutic efficacy against solid tumors. TPC NV binds to tumor cells through TCR, redirects tumor-infiltrating T cells via anti-CD3 antibodies, and reverses immunosuppression with anti-PD-1 antibodies, thereby inducing a broad-spectrum T cell response that effectively eliminates established tumors. Furthermore, epacadostat, an inhibitor of indoleamine 2,3-dioxygenase, can be loaded into TPC NV to suppress regulatory T cell (Treg) generation and enhance dendritic cell (DC) maturation by inhibiting tumor tryptophan metabolism. This dual action amplifies adaptive immune activation and triggers a robust systemic anti-tumor immune response.

项与艾卡哚司他相关的新闻（医药）

2025-10-26

·BioDialectics

华西医院系统阐述肿瘤微环境代谢与免疫的交互机制

肿瘤微环境（TME）中的代谢重编程与免疫细胞功能调控的复杂交互，已成为肿瘤免疫逃逸的核心机制之一。肿瘤细胞通过掠夺营养、积累毒性代谢物构建免疫抑制“壁垒”，而免疫细胞则在代谢压力下呈现“耗竭”或“适应性重塑”的两极分化命运。因此系统剖析了TME中代谢应激、免疫细胞适应及代谢检查点靶向的关键机制，为代谢干预联合免疫治疗的临床转化提供了全景式参考。一：代谢应激—肿瘤免疫抑制的“隐形推手” 肿瘤细胞的快速增殖依赖剧烈的代谢重编程，这种“代谢贪婪”不仅导致TME内营养匮乏，还通过积累毒性代谢产物形成免疫抑制微环境，从多维度抑制抗肿瘤免疫应答： 1. 营养竞争加剧免疫饥饿：肿瘤细胞通过高表达GLUT1等转运体优先消耗葡萄糖，同时掠夺谷氨酰胺、色氨酸、精氨酸等关键氨基酸，导致效应T细胞、NK细胞因能量和生物合成底物不足而功能受损。例如，葡萄糖缺乏会抑制T细胞的mTOR-HIF-1α通路，减少IFN-γ分泌。色氨酸耗竭则通过激活GCN2通路诱导CD8⁺T细胞失能。 2. 毒性代谢物构建“免疫冷区”：肿瘤细胞的有氧糖酵解产生大量乳酸，导致TME酸化，直接抑制CTL的穿孔素聚合和颗粒酶释放。CD39/CD73通路将ATP水解为腺苷，通过A2A受体抑制T/NK细胞增殖。色氨酸经IDO代谢生成的犬尿氨酸（Kyn）可激活AhR通路，促进Treg和MDSC扩增。这些代谢废物共同塑造了免疫细胞难以浸润和激活的“冷肿瘤”微环境。 3. 空间异质性加剧免疫隔离：肿瘤血管异常导致TME内氧和营养分布不均，血管远端区域形成缺氧、低葡萄糖、高乳酸的“免疫盲区”。缺氧与乳酸还会协同诱导癌相关成纤维细胞（CAFs）沉积胶原，形成物理屏障阻碍免疫细胞浸润，进一步巩固免疫抑制格局。二：免疫细胞的代谢适应：耗竭与重塑的两极分化面对TME的极端代谢压力，免疫细胞呈现两种截然不同的命运轨迹，深刻影响抗肿瘤免疫结局： 1.效应免疫细胞的“代谢耗竭” CD8⁺T细胞、NK细胞和树突状细胞（DCs）在营养剥夺和毒性代谢物积累下逐渐丧失功能： 1）T细胞：葡萄糖缺乏与PD-1/CTLA-4信号共同抑制糖酵解，迫使T细胞转向脂肪酸氧化（FAO），伴随内质网应激和线粒体损伤，最终陷入表达TIM-3、LAG-3的耗竭表型。 2）NK细胞：缺氧和乳酸抑制mTOR-HIF-1α轴，降低其细胞毒性颗粒释放和IFN-γ分泌。 3）DCs：氧化脂质积累引发内质网应激，阻碍抗原肽装载，同时乳酸通过GPR81受体抑制IL-12分泌，使其向耐受型表型转化。 2.免疫抑制细胞的“代谢优势” 调节性T细胞（Tregs）、肿瘤相关巨噬细胞（TAMs）和髓系来源抑制细胞（MDSCs）通过灵活的代谢重编程获得生存优势： 1）Tregs：在FoxP3调控下抑制糖酵解、增强氧化磷酸化（OXPHOS），并通过CD36摄取脂肪酸维持FAO，甚至可利用乳酸作为碳源，在低葡萄糖环境中持续发挥免疫抑制作用。 2）TAMs：向M2表型极化后依赖FAO供能，通过CD36摄取氧化低密度脂蛋白，激活COX-2/PGE2通路促进肿瘤进展，同时通过TNF-α反馈环路进一步增强肿瘤乳酸生成。 3）MDSCs：高表达精氨酸酶1（Arg1）和诱导型一氧化氮合酶（iNOS），耗竭微环境中的精氨酸并产生ROS和NO，直接抑制T细胞增殖，同时通过摄取半胱氨酸剥夺T细胞的关键营养。三：被忽视的“代谢护城河”：三级淋巴结构的免疫庇护所三级淋巴结构（TLS）作为TME中的“免疫绿洲”，其独特的代谢微环境为B细胞和T细胞提供了功能维持的关键支撑： 1）TLS通常定位于血管丰富的肿瘤边缘，充足的氧和营养供应形成“代谢护城河”，支持生发中心反应和高亲和力抗体产生。 2）成熟TLS中，B细胞与T细胞通过空间分区和代谢分工减少营养竞争：滤泡中心的B细胞依赖FAO完成抗体合成，而周边T细胞区优先利用葡萄糖，同时通过细胞因子互作（如Tfh细胞分泌IL-21促进B细胞糖酵解）实现功能协同。 3）当TLS的代谢供应被肿瘤生长破坏时，B细胞易向IL-10⁺调节性B细胞（Bregs）转化，反而增强免疫抑制，提示维持TLS代谢稳态是增强免疫治疗疗效的关键环节。四：代谢免疫检查点：超越PD-1/CTLA-4的新型治疗靶点肿瘤通过“酶-代谢物-受体”轴构建的代谢免疫检查点，与经典免疫检查点协同形成双重免疫逃逸屏障，主要包括两类核心通路： 1）营养剥夺型检查点：Arg1/iNOS介导的精氨酸耗竭、IDO介导的色氨酸-Kyn-AhR通路、SLC43A2介导的甲硫氨酸竞争，分别通过抑制T细胞周期进展、激活免疫抑制信号、下调STAT5表达削弱免疫功能。 2）毒性信号累积型检查点：CD39/CD73-腺苷-A2AR通路、MCT/LDH介导的乳酸-GPR81通路，以及LysoPS-GPR34通路（选择性抑制NK细胞功能），通过激活胞内抑制性信号（如cAMP-PKA通路）直接抑制效应免疫细胞活性。值得注意的是，代谢检查点与经典检查点存在协同逃逸机制：PD-1阻断激活的T细胞分泌IFN-γ，反而会诱导肿瘤细胞和髓系细胞上调IDO、CD73表达，通过代谢重编程形成“二次逃逸”，这也解释了单一免疫检查点抑制剂的临床局限性。五：临床转化：代谢干预联合免疫治疗的机遇与挑战尽管单一代谢抑制剂疗效有限，但联合免疫检查点抑制剂（ICIs）已展现出协同潜力，目前多款靶向代谢通路的药物进入临床探索阶段： 1）葡萄糖代谢靶向：二甲双胍通过抑制OXPHOS和mTOR通路，可增强CD8⁺T细胞的细胞因子分泌，其与PD-1抑制剂的联合临床试验正在多种实体瘤中开展。MCT1/2抑制剂（如AZD3965）可减少乳酸外排，恢复T细胞功能，但需警惕对正常免疫细胞的潜在毒性。 2）氨基酸代谢靶向：IDO抑制剂（如epacadostat）联合PD-1抑制剂虽在Ⅲ期临床试验中未达预期，但biomarker分层研究提示其在高Kyn/Trp比值患者中可能获益。精氨酸酶抑制剂（如CB-1158）可恢复T细胞增殖，与PD-1抑制剂联合治疗实体瘤的临床试验已显示初步活性。谷氨酰胺酶抑制剂（如CB-839）可增强肿瘤抗原特异性T细胞激活，在非小细胞肺癌、肾癌中展现联合治疗潜力。 3）腺苷通路靶向：A2AR拮抗剂（如ciforadenant）联合PD-L1抑制剂在肾癌中实现11%的客观缓解率。CD73单克隆抗体（如oleclumab）可抑制腺苷生成，其与Durvalumab的联合治疗在Ⅲ期非小细胞肺癌中显示出持久的疾病控制效果。 4）饮食干预辅助治疗：丝氨酸/甘氨酸限制饮食在晚期结直肠癌中实现25%的客观缓解率。模拟禁食饮食（FMD）联合化疗或免疫治疗，可通过调节代谢微环境增强抗肿瘤疗效，部分晚期患者实现完全缓解。然而，临床转化仍面临诸多挑战：代谢抑制剂的系统性毒性、肿瘤代谢通路的代偿性逃逸、患者代谢表型的异质性等，均需通过生物标志物指导的精准分层、多靶点联合策略和动态疗效监测来解决。总结思考肿瘤代谢与免疫的复杂交互网络，为癌症治疗提供了全新的干预维度。未来的研究需突破单一靶点思维，通过空间代谢组学、单细胞测序等技术解析TME的代谢异质性，开发“代谢重塑-免疫激活-结构破坏”的多维度联合策略。同时，利用合成生物学技术改造免疫细胞的代谢适应性，或通过饮食干预精准调控TME代谢，有望将更多“冷肿瘤”转化为“热肿瘤”。随着对代谢-免疫交互机制的深入解码，代谢干预联合免疫治疗将为攻克实体瘤提供更具针对性的临床解决方案，推动免疫治疗从“泛靶点阻断”向“精准代谢调控”的范式转变。 Metabolic regulation of immunity in the tumor microenvironment. Cell Rep. 2025 Oct 22;44(11):116463. doi: 10.1016/j.celrep.2025.116463.

免疫疗法临床研究细胞疗法

2025-10-13

·FierceBiotech

Moderna posts melanoma data behind decision to say \'I do\' to IDO

Moderna studied two doses of mRNA-4359, which encodes PD-L1 and IDO antigens, in combination with Merck & Co.’s blockbuster oncology drug Keytruda.\n Moderna has shared some of the phase 1/2 data that persuaded it to expand and prioritize development of a cancer candidate, reporting responses in melanoma patients failed by checkpoint inhibitors.The data, which Moderna will present at the 2025 European Society for Medical Oncology Congress later this week, come from 29 patients with relapsed or refractory melanoma. All the patients had advanced after trying at least one PD-1/L1 checkpoint inhibitor. Moderna studied two doses of mRNA-4359, which encodes PD-L1 and IDO antigens, in combination with Merck & Co.’s blockbuster oncology drug Keytruda.The objective response rate was 24% in evaluable patients who received mRNA-4359 intramuscularly every three weeks for up to nine doses. Adding in patients with stable disease resulted in a 60% disease control rate. The trial is yet to reach the median duration of response.Moderna saw responses in six of the nine evaluable patients with PD-L1-positive tumors. Keytruda’s label in melanoma covers all levels of PD-L1, but an expression threshold applies in some other tumor types. Moderna said the subgroup analysis supports PD-L1 as a potential predictive biomarker in a high unmet need population. The data drop follows the publication of monotherapy data last year. Moderna sees targeting PD-L1 and IDO as a way to train the immune system to kill a tumor and tackle the immunosuppression that can limit the impact of immune attacks. Kyle Holen, M.D., head of development, therapeutics and oncology at Moderna, set out how the dual mechanism of action differentiates mRNA-4359 from existing drugs.“Where other checkpoint inhibitors restore non-specific T cell activity, mRNA-4359 encodes two critical immune escape pathways to help generate new, target-directed T cells,” Holen said in a statement. “This could enable broader and more durable immune responses for patients who have not had success with prior lines of therapy.”Multiple companies have identified IDO as a target that could complement PD-1/L1 drugs, but the failure of Incyte’s epacadostat triggered a retreat from programs focused on the enzyme. IO Biotech was among the companies that continued to see a future for IDO. However, a phase 3 study of IO’s cancer vaccine missed its primary endpoint in August, and the FDA later advised the biotech against seeking approval.Rose Loughlin, Ph.D., executive vice president of research at Moderna, commented on the competition at a Bernstein event last month. Noting differences between Moderna and IO’s platforms and antigens, Loughlin said the rival data helped derisk mRNA-4359 and encouraged the mRNA specialist “to continue aggressively developing in that space.”

$Moderna posts melanoma data behind decision to say \'I do\' to IDO$

临床3期临床结果信使RNA疫苗siRNA

2025-06-18

·拜尔迪生物

AbMole推荐：那些在肿瘤代谢/表观遗传研究中的高引抑制剂

代谢异常是肿瘤细胞的生物特征之一，包括氧糖酵解、特殊氨基酸和脂肪酸代谢的紊乱等。这些变化不仅仅为肿瘤的快速生长和转移提供了能量，也驱动了肿瘤和微环境的相互作用。另一方面，表观遗传修饰是基因表达调控的重要机制，包括DNA甲基化、组蛋白修饰和RNA调节等多种形式。肿瘤的发生、发展和转移与遗传和表观遗传变化密切相关。AbMole为大家盘点那些在肿瘤代谢研究和肿瘤表观遗传学研究中最常用到的一些小分子抑制剂。AbMole为全球科研客户提供高纯度、高生物活性的抑制剂、细胞因子、人源单抗、天然产物、荧光染料、多肽、靶点蛋白、化合物库、抗生素等科研试剂，全球大量文献专利引用。图1 糖代谢、脂质代谢、氨基酸代谢的重要靶点[1]一、肿瘤代谢研究1 靶向肿瘤糖代谢的抑制剂葡萄糖为生物合成提供了能量，也是碳骨架的主要来源，细胞中糖代谢包括氧化磷酸化和糖酵解。肿瘤细胞存在Warburg 效应，即主要以有氧糖酵解的形式进行供能，并产生乳酸。一些参与葡萄糖代谢的酶如葡萄糖转运蛋白（GLUT1）、乳酸脱氢酶、PI3K/AKT/mTOR信号通路等是肿瘤代谢研究的热门靶点。2014年，AbMole的两款抑制剂分别被西班牙国家心血管研究中心和美国哥伦比亚大学用于动物体内实验，相关科研成果发表于顶刊 Nature 和 Nature Medicine。抑制葡萄糖摄取可以干扰肿瘤细胞的糖代谢，STF-31（M4970）、BAY-876（M8659）等强效GLUT1抑制剂已被用于多种肿瘤的抑制，BAY-876还对GLUTI具有纳摩尔级的IC50值。2-脱氧-D-葡萄糖（2-DG）（M5140）是一种靶向己糖激酶的糖酵解抑制剂，可显著抑制糖酵解及ATP合成，破坏蛋白质的N-糖基化，增加肿瘤细胞对其他抑制剂的敏感性。3-溴丙酮酸（M9680）则是己糖激酶II的抑制剂，可有效针对肝癌细胞。乳酸脱氢酶（LDHA）是Warburg效应的关键酶，GSK2837808A（M6771）在2.6 nM时即可对LDHA表现出抑制效果，GNE-140（M10743）等也是作用于LDHA的特效抑制剂。2靶向肿瘤氨基酸代谢的抑制剂肿瘤细胞内往往会出现氨基酸代谢的重编程，一般由异常表达的氨基酸代谢酶进行催化，这种变化可进一步促进肿瘤免疫逃逸或者肿瘤细胞的恶性程度。谷氨酰胺代谢是氨基酸代谢的关键，V-9302（M14791）是基于谷氨酰胺骨架开发出的谷氨酰胺类似物，也是一种高效的ASCT2（谷氨酰胺转运蛋白）拮抗剂，可阻断谷氨酰胺的摄取。DON（M2328）则是一种谷氨酰胺分解的抑制剂，对多种谷氨酰胺降解酶如PPAT、PFAS等均具有抑制作用。恶性肿瘤的特征之一是色氨酸分解代谢的增强，而色氨酸是T细胞活化的必备氨基酸，肿瘤细胞通过IDO（吲哚胺2,3-双加氧酶）分解色氨酸促进肿瘤细胞的免疫逃逸，因此Necrostatin-1（M2315）、3-TYP（M8978）、Indoximod (NLG-8189)(M9085)、Navoximod (NLG-919)(M11556)、Epacadostat (INCB024360)（M6136）等IDO抑制剂也被称为免疫代谢类抑制剂。3靶向肿瘤脂质代谢的抑制剂脂质代谢的重编程是一个新发现的恶性肿瘤标志。脂质吸收、储存以及合成的增加发生在各种癌症中，并促进了肿瘤的快速生长。脂肪生成的关键调节因子（SREBPs）、乙酰辅酶A羧化酶（ACC）、脂肪酸合成酶（FASN）和 ATP柠檬酸酯酶（ACLY）等在多种肿瘤细胞中存在表达上调的情况。Fatostatin（M10052）可以抑制SREBPs的活化及其下游的FASN，因此可抑制脂肪的生成，除此之外，Betulin(M3996)、Denifanstat (TVB-2640)（M10746）、Cerulenin（M7704）、TVB-3166（M8622）等抑制剂均可抑制脂质的从头合成。NDI-091143（M9587）、SB-204990（M9614）、Lithium citrate （M3170）等因其高效的ACLY抑制活性已经在抗肿瘤领域中备受关注。铁死亡因作为一种潜在的抗肿瘤靶点而被重点研究，脂质代谢与铁死亡之间也存在着密切的关系，含有多不饱和脂肪酸（PUFA）的脂质是铁死亡发生的基础之一。其中长链酰基辅酶 a 合成酶 4（ACSL4）是铁死亡与脂肪酸代谢的重要交叉靶点，PRGL493（M55207）等ACSL4调节剂对于铁死亡和其抗肿瘤机制的研究具有重要意义。二、肿瘤表观遗传研究针对表观遗传的抑制剂主要包括以下几类：DNA甲基化酶（DNMT）抑制剂、组蛋白去乙酰化酶（HDAC）抑制剂、异柠檬酸脱氢酶（IDH）抑制剂、增强子Zeste同源物2（EZH2）抑制剂以及BET抑制剂。图2 表观遗传的几种修饰类型[2]1DNMT抑制剂DNMT在基因组DNA甲基化中起着至关重要的作用，它含有三个亚类，DNMT1可维持复制过程中甲基化位点的遗传稳定性，DNMT3a和DNMT3b可催化新的甲基化位点形成。DNMT的异常表达与肿瘤的形成高度相关，并且表观遗传也会影响免疫细胞的抗肿瘤功能。目前DNMT抑制剂可分为两类：第一种是核苷类似物（能够组装进DNA从而将DNMTs限制在DNA上），第二种则是非核苷类似物（直接结合DNMTs的催化结构域）；Azacitidine（M2291）、Decitabine（M2052）等属于第一种，而SGI-1027（M3008）、γ-Oryzanol（M10985）、CM-272（M9442）、GSK-3685032（M10528）、GSK-3484862（M13815）等是直接作用于DNMT的抑制剂。2HDAC抑制剂组蛋白去乙酰化酶(Histone Deacetylase,HDAC)是一类蛋白酶,对染色体的结构修饰和基因表达调控发挥着重要的作用，细胞中组蛋白的去乙酰化修饰可导致抑癌基因的表达受阻。HDAC抑制剂可通过提高染色质特定区域组蛋白乙酰化，进而影响相关基因的表达，甚至诱导肿瘤细胞的凋亡。Valproic acid（M9054）、Mocetinostat（M1790）、LMK-235（M4986）、Quisinostat（M2119）、TMP195（M6176）等均是高效的HDAC抑制剂，对HDAC的多种亚型均具抑制效果，具有广泛的抗肿瘤活性。Vorinostat（M1780）、Romidepsin（M2007）、Belinostat（M1670）、Panobinostat（M1748）、Tucidinostat（M6178）等也是重要的HDAC抑制剂，在细胞实验、动物实验等多层次均表现出强效的HDAC抑制活性和抗肿瘤活性。3IDH抑制剂异柠檬酸脱氢酶（IDH）是糖代谢过程中的一种酶，同时也在表观遗传中起到了重要作用，IDH催化产生的α-KG是DNA去甲基化酶和组蛋白去甲基化酶的重要辅酶。IDH突变在肿瘤发展中起关键作用，AGI-5198（M2067）、Enasidenib（M4945）、Ivosidenib（M8958）等是IDH的强效抑制剂，可作用于IDH的不同突变体，如IDH1-R132H、 IDH1- R132C等多种类型的突变。4EZH2抑制剂EZH2主要负责在组蛋白H3的第27位赖氨酸残基（H3K27）上进行三甲基化修饰，从而抑制特定基因的表达。这种修饰在维持细胞稳态、调节干细胞自我更新等方面发挥着重要功能。EZH2的异常表达促进肿瘤的形成和上皮-间质转化基因的表达。Tazemetostat（M2677）、GSK343（M2736）、GSK126（M2114）、UNC1999（M3107）等是EZH2的有效抑制剂，可在纳摩尔级的浓度下抑制EZH2的活性。5BET抑制剂溴结构域和额外末端结构域(bromodomain and extraterminal domain,BET)家族蛋白是新型的抗肿瘤靶点。BET蛋白通过结合组蛋白乙酰化位点，招募相关的转录因子，促进多种疾病相关基因的转录，BET与致癌基因（如MYC、BCL-2）以及促纤维化基因的高表达有关。Apabetalone（M2219）、I-BET151（M2096）、GSK1324726A（M9146）等被开发用于抑制BET的活性，可作用于BET家族的BRD2、BRD3、BRD4等多种亚型。肿瘤的代谢研究和表观遗传学研究是近些年来肿瘤研究方向中的热点，并且已经取得了较好的突破，小分子抑制剂在这个过程中起到了至关重要的作用。AbMole多年来持续聚焦跟进小分子抑制剂的最新科研动态，为全球科研客户提供高纯度、高生物活性的各类小分子抑制剂、激动剂和人源化单抗。以下由AbMole为您推荐：名称目录号靶点2-DGM5140糖代谢AICARM4897DisulfiramM3390AZD3965M5189DaporinadM2287BAY-876M86593-Bromopyruvic acidM9680GSK2837808AM6771FX-11M14457STF-31M49703POM6340DCAM6656AR-C155858M14236GNE-140M10743Necrostatin-1M2315氨基酸代谢CB-839M3003BPTESM5015EpacadostatM6136V-9302M14791IndoximodM9085NavoximodM115563-TYPM8978脂质代谢Atorvastatin hemicalciumM5430SimvastatinM3497FatostatinM10052LovastatinM1575Fluvastatin sodiumM2126OpaganibM9383BetulinM3996TVB-3166M8622OrlistatM3549PRGL493M55207RotenoneM6209MitochondrialFCCPM9051DevimistatM2297MG132M1902ProteasomeBortezomibM1686CarfilzomibM2152EpoxomicinM21935-AzacytidineM2291DNMTCM-272M9442DecitabineM2052GSK-3484862M13815GSK-3685032M10528SGI-1027M3008γ-OryzanolM10985BelinostatM1670HDACLMK-235M4986MocetinostatM1790PanobinostatM1748QuisinostatM2119RomidepsinM2007TMP195M6176TucidinostatM6178Valproic acidM9054VorinostatM1780AGI-5198M2067IDHEnasidenibM4945ivosidenibM8958DZNepM2358EZH2GSK126M2114GSK343M2736TazemetostatM2677UNC1999M3107dBET6M9238BETI-BET151M2096SGC-CBP30M9141BIX-01294M2024HMTChaetocinM6592*本文所述产品均为科研试剂，仅供科学实验用途。AbMole是ChemBridge中国区官方指定合作伙伴。参考文献[1] STINE Z E, SCHUG Z T, SALVINO J M, et al. Targeting cancer metabolism in the era of precision oncology [J]. Nature reviews Drug discovery, 2022, 21(2): 141-62.[2] TAO L, ZHOU Y, LUO Y, et al. Epigenetic regulation in cancer therapy: From mechanisms to clinical advances [J]. MedComm – Oncology, 2024, 3(1).订购咨询北京拜尔迪热线：010-62960866网址：www.biodee.net北京拜尔迪生物(BioDee)，成立于2003年，国家级高新技术企业，多个进口品牌和优秀国产品牌的一级代理商，专注于生命科学领域，为客户提供试剂、耗材、仪器等产品，涵盖了细胞生物学、微生物学、植物学、分子生物学、生物化学、免疫学等领域。

临床1期

100 项与艾卡哚司他相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11049	艾卡哚司他	L01XX58	DB11717

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
非小细胞肺癌	临床3期	美国	Incyte Corp.	2017-12-27
复发性非小细胞肺癌	临床3期	美国	Incyte Corp.	2017-12-27
转移性尿路上皮癌	临床3期	美国	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	日本	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	澳大利亚	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	加拿大	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	丹麦	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	法国	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	德国	Incyte Corp.	2017-12-22
转移性尿路上皮癌	临床3期	匈牙利	Incyte Corp.	2017-12-22

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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


NCT03532295 (CTIM-23, CTgov)	临床2期	多形性胶质母细胞瘤 \| 胶质母细胞瘤 \| 复发性胶质母细胞瘤	51	Radiation therapy+Bevacizumab+Retifanlimab (Regimen A: Retifanlimab+RT+Bevacizumab)	膚簾範鹽糧顧網窪齋選 = 艱襯餘壓鑰糧鑰鹹醖廠餘鑰觸積鬱鏇蓋齋餘醖 (醖繭憲廠範範網齋壓願, 廠鹹膚醖夢襯襯艱醖艱 ~ 鹽淵蓋構獵積積鬱製壓) 更多	-	2025-08-07
				Radiation therapy+Bevacizumab+Epacadostat+Retifanlimab (Regimen B: Retifanlimab+RT+Bevacizumab+Epacadostat)	膚簾範鹽糧顧網窪齋選 = 遞襯醖鏇壓獵糧構顧窪餘鑰觸積鬱鏇蓋齋餘醖 (醖繭憲廠範範網齋壓願, 積鏇糧願蓋鹹範窪鏇繭 ~ 蓋壓遞夢願蓋艱築窪繭) 更多
NCT03414229 (CTgov)	临床2期	恶性纤维组织细胞瘤 \| 平滑肌肉瘤 \| 血管肉瘤 ... 更多	30	Pembrolizumab+Epacadostat (UPS, Liposarcoma or Pleomorphic Liposarcoma)	壓餘鏇獵選憲淵獵醖製 = 齋鬱廠衊蓋鹽製鏇襯鏇獵蓋製鏇醖窪願齋壓鏇 (獵網艱夢構鹽製網簾遞, 選遞繭鑰願獵觸繭鹽鹹 ~ 遞廠夢範構淵蓋艱壓壓) 更多	-	2025-05-02
				Pembrolizumab+Epacadostat (Leiomyosarcoma)	壓餘鏇獵選憲淵獵醖製 = 積網壓積積鏇鹽觸遞糧獵蓋製鏇醖窪願齋壓鏇 (獵網艱夢構鹽製網簾遞, 夢願窪積襯鏇襯齋膚鏇 ~ 顧簾繭積壓獵範獵築壓) 更多
NCT04586244 (Optimus, CTgov)	临床2期	肌层浸润性膀胱尿路上皮癌	30	Epacadostat+Retifanlimab (Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W)	糧觸築壓夢餘築積獵觸 = 餘糧鑰積衊廠構蓋獵積鹹觸鹽鹽構齋艱襯廠範 (襯糧襯鹽醖顧鹹窪糧遞, 鹽簾鏇築獵鹽憲構襯窪 ~ 製壓蓋壓餘鏇獵積窪網) 更多	-	2025-03-10
				Retifanlimab (Retifanlimab 500 mg Q4W)	鬱願淵蓋積淵選製齋廠(膚遞廠鹽窪觸鏇鹽範淵) = 製憲鹹繭願夢餘簾選顧膚衊顧鬱築簾壓積蓋醖 (糧蓋鏇衊憲衊廠鏇積鏇, 0.9332) 更多
NCT03374488 (ECHO-303 \| KEYNOTE-698, Pubmed) 人工标引	临床3期	晚期尿路上皮癌二线	42	Epacadostat 100 mg BID plPembrolizumabmab	衊積遞餘淵糧鬱積範願(鏇淵構齋鏇製顧積範廠) = 憲廠製觸獵獵餘鑰顧鑰膚鑰築築憲積鑰製夢觸 (鏇艱觸鹹願憲糧構遞窪, 16.35 ~ 48.11) 更多	积极	2024-07-25
				Placebo plPembrolizumabmab	衊積遞餘淵糧鬱積範願(鏇淵構齋鏇製顧積範廠) = 鹽鹽窪蓋選窪壓積齋醖膚鑰築築憲積鑰製夢觸 (鏇艱觸鹹願憲糧構遞窪, 4.67 ~ 29.50) 更多
NCT03322540 (Pubmed) 人工标引	临床2期	PD-L1阳性非小细胞肺癌一线 PD-L1	154	pembrolizumab0Epacadostat	觸蓋獵壓鏇膚繭獵網鹽(選鏇獵鑰鏇鹹製築顧壓) = 鹹獵製簾獵鹹鑰鏇構顧願網壓構鑰積餘觸繭夢 (網觸選蓋鹹醖顧淵襯衊, 22.2 ~ 44.1) 更多	不佳	2024-07-25
				pembrolizumab	觸蓋獵壓鏇膚繭獵網鹽(選鏇獵鑰鏇鹹製築顧壓) = 鹹範鏇餘遞繭製範願構願網壓構鑰積餘觸繭夢 (網觸選蓋鹹醖顧淵襯衊, 28.0 ~ 50.8) 更多
NCT03260894 (KEYNOTE-679/ECHO-302, Pubmed) 人工标引	临床3期	转移性肾细胞癌一线	129	Pembrolizumab plus epacadostat	繭築窪構構鹽築鏇齋齋(餘膚積蓋餘觸壓醖醖齋) = 構憲壓蓋淵淵廠淵糧衊襯範顧鬱壓顧觸選夢繭 (窪積淵遞艱繭餘網鹽憲, 20.2 ~ 44.1) 更多	不佳	2024-07-25
				Sunitinib or pazopanib	繭築窪構構鹽築鏇齋齋(餘膚積蓋餘觸壓醖醖齋) = 餘憲艱築構築夢築鑰淵襯範顧鬱壓顧觸選夢繭 (窪積淵遞艱繭餘網鹽憲, 18.6 ~ 41.8) 更多
NCT03358472 (KEYNOTE-669/ECHO-304, Pubmed) 人工标引	临床3期	头颈部鳞状细胞癌	89	Pembrolizumab plus epacadostat	襯憲遞繭積夢範夢鏇遞(觸淵餘壓窪積齋齋遞窪) = 構積醖餘鹹遞範衊壓獵醖觸獵壓餘齋醖觸範鹽 (網憲鑰醖製齋廠糧廠築, 17 ~ 49) 更多	积极	2024-07-25
				Pembrolizumab monotherapy	襯憲遞繭積夢範夢鏇遞(觸淵餘壓窪積齋齋遞窪) = 鏇繭鹽衊餘築觸積繭網醖觸獵壓餘齋醖觸範鹽 (網憲鑰醖製齋廠糧廠築, 6 ~ 46) 更多
NCT03322566 (ECHO-306/KEYNOTE-715, Pubmed) 人工标引	临床2期	转移性非小细胞肺癌一线 PD-L1 tumor proportion score \| tumor histology	178	Epacadostat-Pembrolizumab-Chemotherapy	網淵簾淵鹽願顧觸觸遞(鹹觸壓襯願襯膚齋繭壓) = 願淵窪夢願鬱獵齋範構選築糧淵鏇鏇齋襯築選 (願積糧鏇製醖製積憲鹽, 17.7 ~ 36.7) 更多	不佳	2024-07-25
				Placebo-Pembrolizumab-Chemotherapy	網淵簾淵鹽願顧觸觸遞(鹹觸壓襯願襯膚齋繭壓) = 鹽餘艱積廠餘窪願鹽淵選築糧淵鏇鏇齋襯築選 (願積糧鏇製醖製積憲鹽, 34.1 ~ 55.9) 更多
NCT03361865 (ECHO-307/KEYNOTE-672, Pubmed) 人工标引	临床3期	尿路上皮癌一线 circulating kynurenine levels	93	Epacadostat plus Pembrolizumab	簾膚膚淵艱糧築艱觸廠(構衊齋願鬱衊選遞簾鹽) = 網獵繭鏇願鹹遞構鹽網範顧願觸醖簾積衊獵襯 (齋憲淵壓蓋蓋範製壓壓, 22.46 ~ 55.24) 更多	不佳	2024-07-25
				Placebo plus Pembrolizumab	簾膚膚淵艱糧築艱觸廠(構衊齋願鬱衊選遞簾鹽) = 觸鑰積餘衊鹹遞糧蓋窪範顧願觸醖簾積衊獵襯 (齋憲淵壓蓋蓋範製壓壓, 15.33 ~ 43.67) 更多
NCT03516708 (AACR2024) 人工标引	临床1期	直肠癌	17	epacadostat + SCRT + 6 cycles of CAPOX chemotherapy	衊糧膚憲餘膚繭淵製築(繭齋蓋壓齋蓋襯鏇醖窪) = 鑰鹹繭觸築夢廠顧範壓築鑰範廠繭鑰窪夢齋憲 (網製鬱獵範廠餘顧衊築 ) 更多	积极	2024-04-09