IACS-10759
(Synonyms: 5-(5-甲基-1-(3-(4-(甲基磺酰基)哌啶-1-基)苄基)-1H-1,2,4-三唑-3-基)-3-(4-(三氟甲氧基)苯基)-1,2,4-恶二唑,IACS-10759) 目录号 : GC19194
IACS-10759 (IACS-010759) 是一种氧化磷酸化抑制剂，IACS-10759 是一种有效的氧化磷酸化复合物 I ( OXPHOS ) 抑制剂。
Cas No.:1570496-34-2
Sample solution is provided at 25 µL, 10mM.
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IACS-10759 (IACS-010759) is an oxidative phosphorylation inhibitor, IACS-10759 is a potent inhibitor of complex I of oxidative phosphorylation ( OXPHOS )[1].
IACS-010759 targets glycolysis-deficient tumor cells, In most cell lines, IACS-010759 treatment modestly increased apoptosis by up to twofold[1]. IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp160 in the 49-kDa subunit, located deep in the interior of a previously proposed quinone-access channel[2]. IACS-010759 in complex I is the membrane-embedded ND1 subunit because amino acid substitution at Leu55 (to Phe) in this subunit, which faces the proposed ubiquinone-access channel interior[3].Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools[4]. Inhibition of OxPhos(by IACS-010759) induced transfer of mitochondria derived from mesenchymal stem cells (MSCs) to AML cells via tunneling nanotubes under direct-contact coculture conditions. Inhibition of OxPhos also induced mitochondrial fission and increased functional mitochondria and mitophagy in AML cells[5]. Systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes[8]. In vitro, the combination of AZD3965 and IACS-010759 is synergistic and induces DLBCL cell death, whereas monotherapy treatments induce a cytostatic response[9].
IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma[6].Changes in blood glucose level with single or repeated doses of IACS-010759 did not observe. However, at 2 h after the first or fifth dose, plasma insulin levels transiently decreased and returned to control levels by 24 h postdose[1]. IACS-010759 as an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited melanoma brain metastases (MBM) formation in the spontaneous MBM model[7].
References:
[1]. Molina JR, Sun Y, et,al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018 Jul;24(7):1036-1046. doi: 10.1038/s41591-018-0052-4. Epub 2018 Jun 11. PMID: 29892070.
[2]. Tsuji A, Akao T, et,al.IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism. J Biol Chem. 2020 May 22;295(21):7481-7491. doi: 10.1074/jbc.RA120.013366. Epub 2020 Apr 14. PMID: 32295842; PMCID: PMC7247293.
[3]. Zhu J, Vinothkumar KR, et,al. Structure of mammalian respiratory complex I. Nature. 2016 Aug 18;536(7616):354-358. doi: 10.1038/nature19095. Epub 2016 Aug 10. PMID: 27509854; PMCID: PMC5027920.
[4]. Vangapandu HV, Alston B, et,al.Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells. Oncotarget. 2018 May 18;9(38):24980-24991. doi: 10.18632/oncotarget.25166. PMID: 29861847; PMCID: PMC5982765.
[5]. Saito K, Zhang Q, et,al.Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition. Blood Adv. 2021 Oct 26;5(20):4233-4255. doi: 10.1182/bloodadvances.2020003661. PMID: 34507353; PMCID: PMC8945617.
[6]. Anderson NM, Qin X, et,al. Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma. Cancer Res. 2021 Sep 1;81(17):4417-4430. doi: 10.1158/0008-5472.CAN-20-2153. Epub 2021 Jul 7. PMID: 34233924; PMCID: PMC8577318.
[7]. Fischer GM, Jalali A, et,al. Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases. Cancer Discov. 2019 May;9(5):628-645. doi: 10.1158/2159-8290.CD-18-1489. Epub 2019 Feb 20. PMID: 30787016; PMCID: PMC6497554.
[8]. Jewell BE, Xu A, et,al.Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. PLoS Genet. 2021 Dec 29;17(12):e1009971. doi: 10.1371/journal.pgen.1009971. PMID: 34965247; PMCID: PMC8716051.
[9]. Noble RA, Thomas H, et,al.Simultaneous targeting of glycolysis and oxidative phosphorylation as a therapeutic strategy to treat diffuse large B-cell lymphoma. Br J Cancer. 2022 Sep;127(5):937-947. doi: 10.1038/s41416-022-01848-w. Epub 2022 May 26. PMID: 35618788; PMCID: PMC9428179.
IACS-10759 (IACS-010759) 是一种氧化磷酸化抑制剂，IACS-10759 是一种有效的氧化磷酸化复合物 I ( OXPHOS ) 抑制剂[1]。
IACS-010759 靶向糖酵解缺陷型肿瘤细胞，在大多数细胞系中，IACS-010759 处理适度增加细胞凋亡高达两倍[1]。 IACS-010759 与已知的醌位点抑制剂一样，抑制 Asp160 的甲苯磺酰试剂 AL1 在 49-kDa 亚基中的化学修饰，该亚基位于先前提出的醌访问通道内部深处[2]。复合物 I 中的 IACS-010759 是膜包埋的 ND1 亚基，因为该亚基中 Leu55（至 Phe）的氨基酸取代，它面向拟议的泛醌进入通道内部[3]。初级治疗具有 IACS-010759 的 CLL 细胞极大地抑制了 OxPhos，但在 24 和 48 小时时仅引起轻微的细胞死亡。在存在基质的情况下，该药物成功抑制了 OxPhos 并减少了细胞内核糖核苷酸库[4]。在直接接触共培养条件下，OxPhos（通过 IACS-010759）的抑制通过隧道纳米管诱导间充质干细胞 (MSC) 线粒体转移至 AML 细胞。抑制 OxPhos 还会诱导 AML 细胞中的线粒体分裂并增加功能性线粒体和线粒体自噬[5]。对 IACS-010759 诱导的 RTS 成骨细胞变化的系统分析表明，线粒体呼吸复合物 I 的化学抑制会损害细胞增殖、诱导衰老并减少 MAPK 信号和细胞周期相关基因，但会增加 H19 和核糖体蛋白基因[8 ]。在体外，AZD3965 和 IACS-010759 的组合具有协同作用并诱导 DLBCL 细胞死亡，而单药治疗诱导细胞抑制反应[9]。
IACS-010759 还在斑马鱼和小鼠高危神经母细胞瘤异种移植模型中抑制肿瘤生长[6]。单次或重复给药 IACS-010759 未观察到血糖水平的变化。然而，在第一次或第五次给药后 2 小时，血浆胰岛素水平短暂下降，并在给药后 24 小时恢复到控制水平[1]。 IACS-010759 作为一种 OXPHOS 抑制剂，目前处于早期临床试验阶段，提高了携带 MAPK 抑制剂耐药颅内黑色素瘤异种移植小鼠的存活率，并抑制了自发性 MBM 模型中黑色素瘤脑转移 (MBM) 的形成[7].
| Cell experiment [1]: | |
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Cell lines |
AML cell line |
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Preparation Method |
Each AML cell line was cultured in 123 nM IACS-010759 medium for 72 h. |
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Reaction Conditions |
123nM IACS-010759 for 72 h |
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Applications |
In most cell lines, IACS-010759 treatment modestly increased apoptosis by up to twofold. |
| Animal experiment [1]: | |
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Animal models |
Mouse models of glioblastoma and/or neuroblastoma and AML |
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Preparation Method |
To determine whether the observed in vitro and ex vivo effects predicted in vivo responses in preclinical models at tolerated doses, IACS-010759 can be evaluated in mouse models of glioblastoma and/or neuroblastoma and AML. The PK profile of IACS-010759 was determined in mice following intravenous (0.3mg/kg) and oral (1mg/kg) administration |
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Dosage form |
IACS-010759 intravenous (0.3mg/kg) and oral (1mg/kg) administration |
|
Applications |
Changes in blood glucose level with single or repeated doses of IACS-010759 did not observe. However, at 2 h after the first or fifth dose, plasma insulin levels transiently decreased and returned to control levels by 24 h postdose. |
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References: [1]. Molina JR, Sun Y, et,al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018 Jul;24(7):1036-1046. doi: 10.1038/s41591-018-0052-4. Epub 2018 Jun 11. PMID: 29892070. |
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| Cas No. | 1570496-34-2 | SDF | |
| 别名 | 5-(5-甲基-1-(3-(4-(甲基磺酰基)哌啶-1-基)苄基)-1H-1,2,4-三唑-3-基)-3-(4-(三氟甲氧基)苯基)-1,2,4-恶二唑,IACS-10759 | ||
| Canonical SMILES | FC(F)(F)OC1=CC=C(C2=NOC(C3=NN(CC4=CC(N5CCC(S(=O)(C)=O)CC5)=CC=C4)C(C)=N3)=N2)C=C1 | ||
| 分子式 | C25H25F3N6O4S | 分子量 | 562.56 |
| 溶解度 | DMSO : 62.5 mg/mL (111.10 mM);Water : < 0.1 mg/mL (insoluble) | 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。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7776 mL | 8.8879 mL | 17.7759 mL |
| 5 mM | 0.3555 mL | 1.7776 mL | 3.5552 mL |
| 10 mM | 0.1778 mL | 0.8888 mL | 1.7776 mL |
| 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 | ||||||||||
计算结果:
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >99.50%
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