PF-06840003

PF-06840003 (EOS200271): Indoleamine 2,3-dioxygenase-1 (IDO-1) [1]
PF-06840003 (EOS200271): Indoleamine 2,3-dioxygenase-1 (IDO-1)exhibits good potency in human whole blood IDO-1 assay) [2]

在体外，PF-06840003 可逆转 IDO-1 产生的 T 细胞无反应性[1]。 PF-06840003 在 LPS/INFγ 刺激的 THP1 细胞 (IC50=1.7 μM) 和 HeLa 测试 (IC50=1.8 μM) 中均表现出作用[2]。

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1. PF-06840003在体外可逆转IDO-1诱导的T细胞无能状态，消除IDO-1介导的色氨酸分解代谢对效应T细胞的免疫抑制作用[1]
2. PF-06840003在人全血IDO-1活性实验中表现出良好效价，在生理相关的体外体系中可有效抑制内源性IDO-1活性[2]
3. X射线晶体结构分析显示，PF-06840003以新颖的方式结合人IDO-1，与大多数已报道的IDO-1抑制剂不同，它不与酶的血红素铁原子相互作用[2]

当与免疫检查点抑制剂联合使用时，PF-06840003 可将小鼠瘤内犬尿氨酸水平降低 80% 以上，并在几种临床前同基因小鼠模型中阻止肿瘤生长。 PF-0684003 的预期人体药代动力学特征包括预测 t1/2 为 16-19 小时[1]。

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1. 小鼠口服PF-06840003后，肿瘤内犬尿氨酸（色氨酸分解代谢产物）水平下降超过80%，有效阻断了肿瘤微环境中IDO-1介导的色氨酸代谢[1]
2. PF-06840003与免疫检查点抑制剂联用时，在多个小鼠临床前同基因肿瘤模型中表现出肿瘤生长抑制作用，在肿瘤免疫治疗中显示出协同的体内疗效[1]

1. 为表征PF-06840003与人IDO-1的结合模式，将IDO-1蛋白与该药物形成复合物后开展X射线晶体学实验；解析晶体结构以分析PF-06840003与IDO-1活性位点的空间相互作用，证实其不依赖血红素铁配位的独特结合方式[2]
2. 开展人全血IDO-1活性实验以评估PF-06840003的效价；将全血样本与不同浓度的PF-06840003共处理并刺激IDO-1表达，随后检测色氨酸分解产物（犬尿氨酸）的水平，以此判定药物对内源性IDO-1活性的抑制效果[2]

1. 为研究PF-06840003对IDO-1诱导的T细胞无能的影响，构建IDO-1表达细胞与效应T细胞的体外共培养模型；向细胞体系中加入PF-06840003后，检测T细胞的增殖能力、活化标志物及功能活性，以此判断药物是否可逆转由IDO-1介导的色氨酸耗竭引发的T细胞无能状态[1]

p.o.
Mice

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1. For in vivo efficacy evaluation, syngeneic tumor models were established in mice by implanting murine tumor cells into immunocompetent mice; PF-06840003 was administered orally (formulated as an oral bioavailable preparation) either as a monotherapy or in combination with immune checkpoint inhibitors, with dosing frequencies adjusted to maintain effective drug exposure [1]
2. Tumor growth was monitored regularly by measuring tumor volume over time to evaluate the antitumor efficacy of PF-06840003 combinations; at the end of the experiment, tumor tissues were collected, and intratumoral kynurenine levels were quantified using biochemical assays to assess the inhibition of IDO-1 activity in vivo [1]

1. PF-06840003 is an orally bioavailable small molecule with a favorable ADME profile, including good absorption and metabolic stability [1]
2. The predicted human pharmacokinetic properties of PF-06840003 include a half-life (t1/2) of 16–19 hours, which supports less frequent dosing in clinical settings [1]
3. PF-06840003 exhibits a very favorable ADME profile in preclinical studies, contributing to its predicted favorable human pharmacokinetic characteristics [2]

[1]. PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr4863.

[2]. Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate. J Med Chem. 2017 Dec 14;60(23):9617-9629.

IDO1 Inhibitor PF-06840003 is an orally available hydroxyamidine and inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), with potential immunomodulating and antineoplastic activities. Upon administration, IDO1 inhibitor PF-06840003 targets and binds to IDO1, an enzyme responsible for the oxidation of tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, PF-06840003 increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), natural killer (NK) cells, and T-lymphocytes; PF-06840003 also induces increased interferon (IFN) production, and causes a reduction in tumor-associated regulatory T cells (Tregs). Activation of the immune system, which is suppressed in many cancers, may inhibit the growth of IDO1-expressing tumor cells. IDO1, a cytosolic enzyme responsible for tryptophan catabolism and the conversion of tryptophan into kynurenine, is overexpressed by a variety of tumor cell types and antigen presenting cells (APCs); it plays an important role in immunosuppression. Tryptophan depletion inhibits T-lymphocyte proliferation and activation, and subsequently suppresses the immune system.

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1. Tumors exploit IDO-1 to catabolize tryptophan and accumulate kynurenine, inducing effector T-cell anergy and enhancing Treg function via FoxP3 upregulation; PF-06840003 targets this immunosuppressive pathway by inhibiting IDO-1 activity [1]
2. PF-06840003 is a highly selective IDO-1 inhibitor developed as a clinical candidate for immuno-oncology, with strong potential for combination therapy with immune checkpoint inhibitors [1]
3. The chemical name of PF-06840003 (EOS200271) is 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; it was discovered from a high-throughput screening (HTS) hit (compound 5) and optimized to achieve potent and selective IDO-1 inhibition [2]
4. PF-06840003 has a novel binding mode to human IDO-1, which differentiates it from most other IDO-1 inhibitors that bind to the heme iron atom [2]

C12H9FN2O2

232.21

232.065

198474-05-4

23063810

Light yellow to yellow solid powder

1.713

65.45

2

3

1

17

360

0

MXKLDYKORJEOPR-UHFFFAOYSA-N

InChI=1S/C12H9FN2O2/c13-6-1-2-10-7(3-6)9(5-14-10)8-4-11(16)15-12(8)17/h1-3,5,8,14H,4H2,(H,15,16,17)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (10.77 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (10.77 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (10.77 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。