吲哚胺2,3-双加氧酶1(IDO1)抑制剂的研究进展

吲哚胺2,3-双加氧酶1 (indoleamine 2,3-dioxygenase 1,IDO1)是代谢色氨酸转化为犬尿氨酸的限速酶.其在肿瘤组织中过表达,造成肿瘤微环境中的色氨酸耗竭,从而抑制T细胞功能,介导肿瘤的免疫逃逸,是潜在的肿瘤免疫治疗靶点.目前,多个IDO1抑制剂处于临床研究阶段.本文主要介绍IDO1介导肿...     

吲哚胺2,3-双加氧酶的研究进展

吲哚胺2,3双加氧酶（IDO）是色氨酸沿犬尿酸途径分解代谢的限速酶,在多种肿瘤组织中均有较高的表达,其高表达是导致肿瘤免疫耐受的原因之一,与肿瘤患者的预后较差关系密切。目前,学者们观点比较一致的是, IDO可通过3种机制参与诱导肿瘤微环境中的免疫耐受。脂多糖和多种细胞因子等物质可调节IDO的表达,1-甲基色氨酸作为IDO的抑制剂在肿瘤患者的免疫治疗中显示出了积极的作用,因此对IDO如何参与肿瘤免疫耐受具体机制的进一步研究,将会对今后制定肿瘤治疗策略具有重要的指导意义。     

吲哚胺2,3-双加氧酶在肿瘤及肿瘤耐药中的研究现状

吲哚胺2,3-双加氧酶(IDO)是一种肝外催化色氨酸沿犬尿氨酸途径降解的限速酶。IDO抑制药被用在不同恶性肿瘤及耐药肿瘤治疗的相关实验中,特别是与放疗和化疗相结合时取得了良好的效果。本文将对IDO及其抑制药对肿瘤及肿瘤耐药的影响进行综述。     

新型吲哚胺2,3-双加氧酶1抑制剂的合成及活性研究

目的设计合成2类1H-吲唑类新化合物,并测试其吲哚胺2,3-双加氧酶1(IDO1)抑制活性。方法以肿瘤免疫关键调控蛋白IDO1作为靶标,依据IDO1活性位点的关键药效团特征,利用合理药物设计方法,以前期研究获得的高活性化合物作为先导化合物,设计合成了2类1H-吲唑类衍生物,并测试其体外IDO1酶抑制活性。采用分子对接软件DOCK6进行分子对接模拟并分析化合物的构效关系。结果与结论合成了5个1H-吲唑类衍生物,均表现出不同程度的IDO1抑制活性,其中化合物2a和3b的抑制活性较好,在100μmol·L~(-1)时的抑制率均为69%。构效关系和分子对接研究显示,4位连接基团的结构对化合物活性影响很大,1H-吲唑类化合物还有很大结构优化空间,极具开发潜力,可为靶向IDO1的肿瘤免疫治疗提供候选化合物。     

治疗膀胱癌的吲哚胺2,3-双加氧酶1抑制剂—Linrodostat

膀胱癌是泌尿系统最常见的恶性肿瘤之一,占我国泌尿生殖系统肿瘤发病率的第1位.吲哚胺2,3-双加氧酶1(IDO1)是一种细胞溶质酶,可以改善肿瘤微环境而使肿瘤细胞产生免疫抑制,Linrodostat是一种强效的IDO1口服抑制剂.在Ⅰ、Ⅱ期临床试验中,Linrodostat对人IDO1表现出很强的效力,并且在测试剂量下并...     

吲哚胺2，3-双加氧酶的表达与宫颈癌发生和病理进程的关系研究

目的：探讨吲哚胺2,3-双加氧酶（IDO）的表达情况与女性宫颈癌的发生与病理进程的相关性。方法选取宫颈癌手术治疗后的石钠组织标本75例（宫颈癌组）,宫颈上皮瘤变Ⅰ级标本30例（CINⅠ级组）、宫颈上皮瘤变Ⅱ~Ⅲ级标本30例（CINⅡ~Ⅲ级组）、体检收集的正常宫颈标本30例（正常组）,采用免疫组织化学法检测各组样本中的 IDO 阳性表达率,并追踪观察 IDO 表达与宫颈癌患者病理及生存与后的关系。结果宫颈癌组标本的 IDO 阳性表达率显著的高于 CINⅠ级组、CINⅡ~Ⅲ级组和正常组（ P <0.05）;CINⅡ~Ⅲ级组 IDO 阳性表达率显著的高于正常组（ P <0.05）。低分化宫颈癌患者、Ⅲ+Ⅳ期宫颈癌患者、发生淋巴结转移的宫颈癌患者的 IDO 阳性率表达显著的增高,IDO 阳性表达与患者的分化程度、FIGO 分期、淋巴结转移具有一定的关系（P <0.05）。经过36个月的随访,IDO 阳性表达53例患者中有7例死亡、2例失访,IDO 阴性表达患者22例中有3例死亡,1例失访,IDO 表达阳性与阴性患者的3年病死率差异无统计学意义（ P >0.05）;IDO 阴性表达患者的3年生存中位时间35.4个月与 IDO 阳性表达患者的34.2个月差异无统计学意义（ P >0.05）。结论 IDO 在宫颈癌组织中高表达,与宫颈癌的分化程度、FIGO 分期、淋巴结转移具有一定的关系,与患者的3年生存预后关系不显著,需进一步延长随访时间进行观察。     

槲皮素通过影响吲哚胺-2,3-双加氧酶活性抑制HeLa细胞增殖的研究

目的研究槲皮素抑制人宫颈癌HeLa细胞增殖的机制。方法采用CCK-8法检测细胞增殖;流式细胞术检测细胞周期的变化;运用紫外可见分光光度计测定OD₄₈₀值,反映色氨酸代谢及犬尿氨酸的生成情况;qPCR法检测IDO1的mRNA表达;表达、纯化IDO1蛋白并进行体外酶活性反应,用高效液相色谱法检测色氨酸和犬尿氨酸的含量变化。结果槲皮素抑制HeLa细胞的增殖,引起G0/G1细胞周期阻滞;槲皮素抑制色氨酸的代谢;槲皮素能够明显抑制IDO1的体外酶催化活性,但不影响IDO1的表达;外源性添加色氨酸的代谢产物犬尿氨酸可以逆转槲皮素引起的细胞增殖抑制。结论槲皮素可能通过抑制IDO1的酶催化活性,影响细胞色氨酸的代谢,这可能是槲皮素发挥其抗宫颈癌HeLa细胞增殖作用的机制之一。     

新型吲哚胺2,3-二加氧酶抑制剂及其治疗人类疾病的研究

吲哚胺2,3-二加氧酶(indoleamine 2,3-dioxygenase,IDO)是催化色氨酸沿犬尿氨酸代谢途径分解的限速酶,已被证实与肿瘤、阿尔茨海默病、抑郁症和白内障等多种人类疾病的发病机制密切相关.IDO抑制剂是具有新药靶、新机制的广谱药物,应用前景非常广阔.     

Discovery and Preclinical Evaluation of BMS-986242, a Potent,Selective Inhibitor of Indoleamine-2,3-dioxygenase 1

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.     

Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1

Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers. Indoleamine 2,3-dioxygenase 1 (IDO1), an immune checkpoint, plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy. Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a new model for drug research and development for its advantageous mechanism. Herein, we reported the application of PROTAC technology in targeted degradation of IDO1, leading to the discovery of the first IDO1 PROTAC degrader 2c, which induced significant and persistent degradation of IDO1 with maximum degradation (d_max) of 93% in HeLa cells. Western-blot based mechanistic studies indicated that IDO1 was degraded by 2c through the ubiquitin proteasome system (UPS). Label-free real-time cell analysis (RTCA) indicated that 2c moderately improved tumor-killing activity of chimeric antigen receptor-modified T (CAR-T) cells. Collectively, these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.     

Discovery of Imidazopyridines as Potent Inhibitors of Indoleamine 2,3-Dioxygenase 1 for Cancer Immunotherapy

Indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as a target for small-molecule immunotherapy for the treatment of a variety of cancers including renal cell carcinoma and metastatic melanoma. This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.     

丁酸钠抑制人鼻咽癌上皮细胞CNE2中吲哚胺双加氧酶表达的体外研究

目的:研究丁酸钠(NaB)抑制人鼻咽癌上皮细胞CNE2中吲哚胺双加氧酶(IDO)表达的分子机制。方法:体外培养CNE2细胞,采用蛋白印迹法、免疫组化法检测不同浓度NaB对重组人干扰素γ(IFN-γ)诱导后CNE2细胞中IDO的表达及NaB作用不同时间对核转录因子STAT1磷酸化的影响;利用pSTAT1-GFP转染CNE2细胞,观察NaB对STAT1核内分布的影响;采用蛋白印迹法检测组蛋白去乙酰化酶抑制剂CAY10398对IDO表达的影响;采用免疫沉淀法检测NaB对转染细胞的STAT1质粒的乙酰化作用。结果:随NaB或CAY10398浓度增加,CNE2细胞中IDO表达均减少;随NaB作用时间延长,IFN-γ诱导下的STAT1磷酸化水平降低;NaB使IFN-γ诱导的细胞核内STAT1绿色荧光蛋白减少;NaB能明显增强转染和未转染细胞中STAT1的乙酰化作用(P<0.001)。结论:NaB抑制CNE2细胞IDO表达的机制可能与其乙酰化STAT1、降低STAT1的磷酸化和核内转移有关。     

Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors

IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.