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
An orally bioavailable inhibitor of mitochondrial complex I
Cas No.:1570496-34-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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 [2]: | |
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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 |
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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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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].
| 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。
Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer
Cancer Res2021 Nov 1;81(21):5572-5581.PMID: 34518211DOI: 10.1158/0008-5472.CAN-20-3242
Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.
Drugging OXPHOS Dependency in Cancer
Cancer Discov2019 Aug;9(8):OF10.PMID: 31186236DOI: 10.1158/2159-8290.CD-ND2019-005
Researchers at The University of Texas MD Anderson Cancer Center in Houston are developing an inhibitor of oxidative phosphorylation, IACS-10759, that targets complex I of the mitochondrial electron transport chain. Ongoing early clinical studies indicate that IACS-10759 appears safe, tolerable, and active; the drug has also shown efficacy in mouse models of ibrutinib-resistant mantle cell lymphoma.
Subtype and site specific-induced metabolic vulnerabilities in prostate cancer
Mol Cancer Res2022 Sep 16;MCR-22-0250.PMID: 36112348DOI: 10.1158/1541-7786.MCR-22-0250
Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive-variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759's inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone. Implications: These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.