IM156
(Synonyms: HL156A; HL271 acetate) 目录号 : GC60201
A mitochondrial complex I inhibitor and an AMPKα activator
Cas No.:1422365-94-3
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
IM-156 is an inhibitor of mitochondrial complex I, also known as NADH dehydrogenase (IC50 = 2.2 ?M) and an activator of AMP-activated protein kinase α (AMPKα).1,2 It reduces the oxygen consumption rate (OCR; IC50 = 3.3 ?M) and decreases mitochondrial ATP production in E?-Myc mouse lymphoma cells.1 IM-156 (10, 30, and 50 ?M) increases AMPKα activity in primary rat peritoneal mesothelial cells and protects against chlorhexidine-induced peritoneal fibrosis in rats when administered at a dose of 1 mg/kg.2 It reduces tumor growth in an AT-84 murine oral cancer model and decreases age-related decline in novel object recognition, spatial working, and contextual memory in mice.3,4
1.Izreig, S., Gariepy, A., Kaymak, I., et al.Repression of LKB1 by miR-17~92 sensitizes MYC-dependent lymphoma to biguanide treatmentCell Rep. Med.1(2)100014(2020) 2.Ju, K.D., Kim, H.J., Tsogbadrakh, B., et al.HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosisAm. J. Physiol. Renal. Physiol.310(5)F342-F350(2016) 3.Lam, T.G., Jeong, Y.S., Kim, S.-A., et al.New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathwaysCancer Sci.109(3)699-709(2018) 4.Bang, E., Lee, B., Park, J.-O., et al.The improving effect of HL271, a chemical derivative of metformin, a popular drug for type II diabetes mellitus, on aging-induced cognitive declineExp. Neurobiol.27(1)45-56(2018)
| Cas No. | 1422365-94-3 | SDF | |
| 别名 | HL156A; HL271 acetate | ||
| Canonical SMILES | N=C(N1CCCC1)NC(NC2=CC=C(OC(F)(F)F)C=C2)=N.CC(O)=O | ||
| 分子式 | C15H20F3N5O3 | 分子量 | 375.35 |
| 溶解度 | DMSO: 100 mg/mL (266.42 mM) | 储存条件 | 4°C, protect from light |
| 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 | 2.6642 mL | 13.3209 mL | 26.6418 mL |
| 5 mM | 0.5328 mL | 2.6642 mL | 5.3284 mL |
| 10 mM | 0.2664 mL | 1.3321 mL | 2.6642 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。
IM156, a new AMPK activator, protects against polymicrobial sepsis
J Cell Mol Med 2022 Jun;26(12):3378-3386.PMID:35502484DOI:10.1111/jcmm.17341.
IM156, a novel biguanide with higher potency of AMP-activated protein kinase activation than metformin, has inhibitory activity against angiogenesis and cancer. In this study, we investigated effects of IM156 against polymicrobial sepsis. Administration of IM156 significantly increased survival rate against caecal ligation and puncture (CLP)-induced sepsis. Mechanistically, IM156 markedly reduced viable bacterial burden in the peritoneal fluid and peripheral blood and attenuated organ damage in a CLP-induced sepsis model. IM156 also inhibited the apoptosis of splenocytes and the production of inflammatory cytokines including IL-1β, IL-6 and IL-10 in CLP mice. Moreover, IM156 strongly inhibited the generation of reactive oxygen species and subsequent formation of neutrophil extracellular traps in response to lipopolysaccharide in neutrophils. Taken together, these results show that IM156 can inhibit inflammatory response and protect against polymicrobial sepsis, suggesting that IM156 might be a new treatment for sepsis.
Modulation of Oxidative Phosphorylation with IM156 Attenuates Mitochondrial Metabolic Reprogramming and Inhibits Pulmonary Fibrosis
J Pharmacol Exp Ther 2021 Nov;379(3):290-300.PMID:34593558DOI:10.1124/jpet.121.000811.
Metabolic reprogramming of the myofibroblast plays a fundamental role in the pathogenesis of fibrosing interstitial lung diseases. Here, we characterized the in vitro and in vivo metabolic and antifibrotic effects of IM156, an oxidative phosphorylation (OXPHOS) modulator that acts by inhibiting protein complex 1. In vitro, IM156 inhibited transforming growth factor β (TGFβ)-dependent increases in mitochondrial oxygen consumption rate and expression of myofibroblast markers in human pulmonary fibroblasts without altering cell viability or adding to TGFβ-induced increases in the extracellular acidification rate. IM156 significantly increased cellular AMP-activated protein kinase (AMPK) phosphorylation and was 60-fold more potent than metformin. In vivo, chronic oral administration of IM156 was highly distributed to major peripheral organs (i.e., lung, liver, kidney, heart) and had significant dose-related effects on the plasma metabolome consistent with OXPHOS modulation and AMPK activation. IM156 increased glycolysis, lipolysis, β-oxidation, and amino acids and decreased free fatty acids, tricarboxylic acid cycle activity, and protein synthesis. In the murine bleomycin model of pulmonary fibrosis, daily oral administration of IM156, administered 7 days after lung injury, attenuated body/lung weight changes and reduced lung fibrosis and inflammatory cell infiltration. The plasma exposures of IM156 were comparable to well tolerated doses in human studies. In conclusion, the metabolic and antifibrotic effects of IM156 suggest that OXPHOS modulation can attenuate myofibroblast metabolic reprogramming and support testing IM156 as a therapy for idiopathic pulmonary fibrosis and other fibrotic diseases. SIGNIFICANCE STATEMENT: Fibrosing interstitial lung diseases have a poor prognosis, and current antifibrotic treatments have significant limitations. This study demonstrates that attenuation of fibrogenic metabolic remodeling, by modulation of oxidative phosphorylation with IM156, prevents myofibroblast phenotype/collagen deposition and is a potentially effective and translational antifibrotic strategy.
First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors
Invest New Drugs 2022 Oct;40(5):1001-1010.PMID:35802288DOI:10.1007/s10637-022-01277-9.
Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.
The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus
Kidney Int 2023 Feb;103(2):343-356.PMID:36332729DOI:10.1016/j.kint.2022.09.031.
Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19+B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity.
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment
Cell Rep Med 2020 May 19;1(2):100014.PMID:32478334DOI:10.1016/j.xcrm.2020.100014.
Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies.