PF-06446846 hydrochloride具有口服活性的前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）翻译抑制剂。
Cas No.:1632250-50-0
Sample solution is provided at 25 µL, 10mM.
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PF-06446846 hydrochloride is an orally active proprotein convertase subtilisin/kexin type 9 (PCSK9) translation inhibitor[1-2]. PF-06446846 hydrochloride selectively inhibits PCSK9 synthesis by inducing ribosomal stalling near codon 34. PF-06446846 hydrochloride can be used in research related to atherosclerosis and cancer[3-4].
In vitro, in a HepG2 and AFP-specific TCR-T cell co-culture system, PF-06446846 hydrochloride (10μM) treatment of TCR-T cells for 12 hours, PF-06446846 hydrochloride enhanced the killing activity of TCR-T cells against hepatocellular carcinoma cells, downregulated PD-1 expression on the T cell surface, and promoted CD8+ T cell activation by upregulating the LDLR-mediated mTORC1 signaling pathway[5]. PF-06446846 hydrochloride (100μM) pretreatment of OVCAR3 and HeLa cells for 48 hours, PF-06446846 hydrochloride significantly inhibited PCSK9 expression and reduced cell survival[6].
In vivo, in the MFC gastric cancer model using 615-line male mice, PF-06446846 hydrochloride (5mg/kg/day) was administered intraperitoneally from day 2 after tumor inoculation (every other day for a total of 10 injections). PF-06446846 hydrochloride significantly inhibited tumor growth and reduced tumor weight, while upregulating MHC-II expression on dendritic cells and tumor cells in the tumor microenvironment and enhancing CD8+ T cell infiltration and functional activation[7]. In the B16F10-OVA melanoma model in C57BL/6 mice, PF-06446846 hydrochloride (5mg/kg) was administered intraperitoneally from day 2 after tumor inoculation (every other day for a total of 8 injections). When used in combination with the OVA-II long peptide vaccine (10μg/mouse; administered subcutaneously from day 3), PF-06446846 hydrochloride significantly enhanced the monotherapeutic anti-tumor efficacy of the OVA-II vaccine, achieving superior tumor control[8].
References:
[1] Liaud N, Horlbeck MA, Gilbert LA, et al. Cellular response to small molecules that selectively stall protein synthesis by the ribosome. PLoS Genet. 2019 Mar 15;15(3):e1008057.
[2] Li W, Ward FR, McClure KF, et al. Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule. Nat Struct Mol Biol. 2019 Jun;26(6):501-509.
[3] Aspnes GE, Coffey SB, Darout E, et al. Small molecule inhibitors of PCSK9. SAR investigations of head and amine groups. Bioorg Med Chem Lett. 2023 Aug 15;92:129394.
[4] Zhang D, Li Q, Chen X, et al. An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy. Small. 2022 Aug;18(32):e2202663.
[5] Xu W, Hu M, Lu X, et al. Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy. Int J Biol Sci. 2024 Jul 15;20(10):3942-3955.
[6] Jacome Sanz D, Raivola J, Karvonen H, et al. Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors. Cancers (Basel). 2021 Jul 24;13(15):3727.
[7] Wang H, Zhang X, Zhang Y, et al. Targeting PCSK9 to upregulate MHC-II on the surface of tumor cells in tumor immunotherapy. BMC Cancer. 2024 Apr 10;24(1):445.
[8] Lintner NG, McClure KF, Petersen D, et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol. 2017 Mar 21;15(3):e2001882.
PF-06446846 hydrochloride具有口服活性的前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）翻译抑制剂[1-2]。PF-06446846 hydrochloride可通过诱导核糖体在密码子34附近停滞，从而选择性抑制PCSK9的合成，PF-06446846 hydrochloride可用于动脉粥样硬化和癌症的相关研究[3-4]。
在体外，在HepG2与AFP特异性TCR-T细胞共培养体系中，PF-06446846 hydrochloride（10μM）处理TCR-T细胞12小时可增强TCR-T细胞对肝癌细胞的杀伤作用，并下调T细胞表面PD-1表达，同时通过上调LDLR介导的mTORC1信号通路促进CD8+ T细胞活化[5]。PF-06446846 hydrochloride（100μM）预处理OVCAR3和HeLa细胞48小时，PF-06446846 hydrochloride显著抑制PCSK9表达并降低细胞存活率[6]。
在体内，在615系雄性小鼠MFC胃癌模型中，PF-06446846 hydrochloride（5mg/kg/day）从肿瘤接种后第2天开始腹腔注射给药（每隔一天一次，共10次），PF-06446846 hydrochloride显著抑制肿瘤生长并降低肿瘤重量，同时上调肿瘤微环境中树突状细胞和肿瘤细胞表面的MHC-II表达，增强CD8+ T细胞的浸润和功能活化[7]。在C57BL/6小鼠B16F10-OVA黑色素瘤模型中，PF-06446846 hydrochloride（5mg/kg）从肿瘤接种后第2天开始腹腔注射给药（每隔一天一次，共8次）联合OVA-II长肽疫苗（10μg/只；从第3天开始皮下注射），PF-06446846 hydrochloride显著增强OVA-II疫苗的单药抗肿瘤疗效，实现更好的肿瘤控制[8]。
| Cell experiment [1]: | |
Cell lines | OVCAR3, OVCAR3cis, A2780, A2780cis, JHOS2, Kuramochi, Ovsaho, COV362, and HeLa cells (human ovarian cancer cell lines and cervical carcinoma cell line) |
Preparation Method | Cells were cultured in RPMI 1640 or DMEM supplemented with 10-20% fetal bovine serum (FBS) and maintained at 37°C, 5% CO₂. Cells were treated with PF-06446846 hydrochloride at 100 for 48 hours. |
Reaction Conditions | 100μM; 48h |
Applications | PF-06446846 hydrochloride significantly impaired ovarian cancer cell survival, with HeLa, OVCAR3, and OVCAR3cis cells showing reduced viability, while PCSK9-negative JHOS2 cells exhibited minimal sensitivity. PF-06446846 hydrochloride treatment also induced robust phosphorylation of AKT, ERK1/2, and MEK1/2 upon PCSK9 overexpression, indicating a pro-survival role of PCSK9 in ovarian cancer cells. |
| Animal experiment [2]: | |
Animal models | 615-line mice and C57BL/6 mice |
Preparation Method | MFC gastric cancer cells were subcutaneously implanted into 615-line mice. B16F10-OVA melanoma cells were subcutaneously implanted into C57BL/6 mice. Mice were intraperitoneally administered PF-06446846 hydrochloride (5mg/kg) every other day for 10-18 days. Mice were sacrificed at the treatment endpoint for tumor analysis. |
Dosage form | 5mg/kg; i.p.; Every other day for 10-18 injections. |
Applications | PF-06446846 hydrochloride significantly suppressed tumor growth in both gastric cancer and melanoma models, reducing tumor volumes and weights. The inhibitor upregulated MHC-II expression on dendritic cells and tumor cells in the tumor microenvironment, enhanced CD8+ T cell infiltration and activation, and improved the anti-tumor efficacy of OVA-II peptide vaccines when used in combination therapy. |
References: | |
| Cas No. | 1632250-50-0 | SDF | |
| Canonical SMILES | O=C(N(C1=NC=CC=C1Cl)[C@H]2CNCCC2)C3=CC=C(N4N=NC5=CC=CN=C54)C=C3.[H]Cl.[x] | ||
| 分子式 | C22H20ClN7O.xHCl | 分子量 | |
| 溶解度 | DMSO : 250 mg/mL (531.52 mM); H2O : 100 mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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