IM156 | CAS#1422365-93-2 | OxPhos inhibitor

MedKoo Cat#: 207129 | Name: IM156

Description:

WARNING: This product is for research use only, not for human or veterinary use.

IM156 is an oxidative phosphorylation inhibitor. IM156 is an orally bioavailable biguanide compound and mitochondrial oxidative phosphorylation (OxPhos) inhibitor, with potential antineoplastic activity. M156 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.

Chemical Structure

IM156

CAS#1422365-93-2 (free base)

Theoretical Analysis

MedKoo Cat#: 207129

Name: IM156

CAS#: 1422365-93-2 (free base)

Chemical Formula: C13H16F3N5O

Exact Mass: 315.1307

Molecular Weight: 315.30

Elemental Analysis: C, 49.52; H, 5.12; F, 18.08; N, 22.21; O, 5.07

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship
500mg	USD 2,850.00	Ready to ship
1g	USD 4,250.00	Ready to ship

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Related CAS #

1422365-52-3 (HCl) 1422365-93-2 (free base) 1422365-94-3 (acetate) 2043654-64-2 (TFA) 2043654-70-0 (malonate) 2043654-72-2 (furmate) 2043654-97-1 (tosylate) 2043654-98-2 (mesylate)

Synonym

IM156; IM-156; IM 156; lixumistat

IUPAC/Chemical Name

N-[Imino[[4-(trifluoromethoxy)phenyl]amino]methyl]-1-pyrrolidinecarboximidamide

InChi Key

NGFUHJWVBKTNOE-UHFFFAOYSA-N

InChi Code

InChI=1S/C13H16F3N5O/c14-13(15,16)22-10-5-3-9(4-6-10)19-11(17)20-12(18)21-7-1-2-8-21/h3-6H,1-2,7-8H2,(H4,17,18,19,20)

SMILES Code

N=C(N1CCCC1)NC(NC2=CC=C(OC(F)(F)F)C=C2)=N

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Mitochondrial OxPhos is overactivated in cancer cells and plays a key role in tumor cell proliferation. Drug resistant tumor cells are very susceptible to decreased mitochondrial OxPhos as they cannot easily compensate for the decrease in mitochondrial function by increasing glycolysis

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A20T10K29

QC Data

View QC data: current batch, Lot#A20T10K29

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

IM156 is a biguanide compound and mitochondrial oxidative phosphorylation (OxPhos) inhibitor, with potential antineoplastic activity.

In vitro activity:

The biological properties of phenformin and the newly developed biguanide IM156, which are more hydrophobic and therefore potentially more bioavailable to cells than metformin (Figure 1A), were investigated. To test the impact of these biguanides on tumor cell respiration, Myc-dependent mouse lymphoma cells (Eμ-Myc cells) were acutely treated with either metformin, phenformin, or IM156 and assessed changes in the oxygen consumption rate (OCR) using the Seahorse XF96 extracellular flux analyzer. Across a range of concentrations, phenformin and IM156 decreased OCR (Figure 1B), with IM156 exhibiting greater potency than phenformin and metformin at equal concentrations. IM156 was more effective than phenformin at reducing cellular ATP production at equal concentrations, correlating with the effect of IM156 on oxidative phosphorylation (Figure 1C). These data are consistent with IM156 functioning as a more potent inhibitor of mitochondrial respiration than phenformin. IM156 also reduced NADH oxidation in purified complex I in a dose-dependent manner (Figure S1A). To further confirm the specificity of IM156 for complex I, the IM156-mediated inhibition of OCR was assessed in cells expressing NDI1, a yeast NADH dehydrogenase that is resistant to biguanides.28 NDI1 expression rescued the effects of IM156 on cellular respiration, promoting an ∼100-fold shift in the IC50 of IM156 (Figure 1E). These data support that IM156 blocks OXPHOS through the inhibition of complex I and does so more potently than phenformin. Reference: Cell Rep Med. 2020 May 19;1(2):100014. https://pubmed.ncbi.nlm.nih.gov/32478334/.

In vivo activity:

In this study, it was investigated how IM156 treatment affects antigen-specific CD8+ T cell differentiation in vivo during acute infection with acute lymphocytic choriomeningitis virus (LCMV) in five- to 6-wk-old female C57BL/6 mice. To examine whether in vivo treatment of IM156 affects the function of memory T cells, splenocytes obtained at day 30 post-infection were re-stimulated ex vivo with the virus-specific peptide GP33-41 for CD8+ T cells and GP66-80 for CD4+ T cells. The percentage and expression levels of TNF-α- and IL-2-producing cells among IFN-γ+CD8+ T cells decreased dose-dependently in the IM156-treated group (Fig. 4A and B). Similar results were observed for IFN-γ+CD4+ T cells in IM156-treated mice (Fig. 4C and D). It has been reported that CD107a represents cytotoxic CD8+ and CD4+ T cell responses to viral and tumor antigen associated with T cell cytolytic potential (16,17,18,19). However, there was no difference in CD107a expression on CD8+ and CD4+ T cells after in vivo treatment with various doses of IM156, indicating that IM156 does not affect the cytotoxicity of T cells (Supplementary Fig. 2). Although the cytotoxic potential was not altered by IM156, the polyfunctionality of CD8+ and CD4+ T cells was significantly decreased after IM156 treatment as shown in Fig. 4, suggesting that IM156 modulates the ability of T cells to produce effector cytokines but not their cytotoxicity after viral infection. Reference: Immune Netw. 2019 Apr; 19(2): e11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494768/

	Solvent	mg/mL	mM
Solubility
	DMSO	30.0	95.15
	Ethanol	20.0	63.43

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 315.30 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Izreig S, Gariepy A, Kaymak I, Bridges HR, Donayo AO, Bridon G, DeCamp LM, Kitchen-Goosen SM, Avizonis D, Sheldon RD, Laister RC, Minden MD, Johnson NA, Duchaine TF, Rudoltz MS, Yoo S, Pollak MN, Williams KS, Jones RG. Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment. Cell Rep Med. 2020 May 19;1(2):100014. doi: 10.1016/j.xcrm.2020.100014. PMID: 32478334; PMCID: PMC7249503. 2. Son J, Cho YW, Woo YJ, Baek YA, Kim EJ, Cho Y, Kim JY, Kim BS, Song JJ, Ha SJ. Metabolic Reprogramming by the Excessive AMPK Activation Exacerbates Antigen-Specific Memory CD8+ T Cell Differentiation after Acute Lymphocytic Choriomeningitis Virus Infection. Immune Netw. 2019 Mar 5;19(2):e11. doi: 10.4110/in.2019.19.e11. PMID: 31089438; PMCID: PMC6494768.

In vitro protocol:

In vivo protocol:

1: Shim JS, Kim EJ, Lee LE, Kim JY, Cho Y, Kim H, Kim J, Jang SH, Son J, Cheong JH, Kim A, Lim BJ, Ha SJ, Song JJ, Kim BS. 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. doi: 10.1016/j.kint.2022.09.031. Epub 2022 Nov 1. PMID: 36332729. 2: Janku F, Beom SH, Moon YW, Kim TW, Shin YG, Yim DS, Kim GM, Kim HS, Kim SY, Cheong JH, Lee YW, Geiger B, Yoo S, Thurston A, Welsch D, Rudoltz MS, Rha SY. 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. doi: 10.1007/s10637-022-01277-9. Epub 2022 Jul 8. PMID: 35802288; PMCID: PMC9395488. 3: Kang JH, Lee SK, Yun NJ, Kim YS, Song JJ, Bae YS. IM156, a new AMPK activator, protects against polymicrobial sepsis. J Cell Mol Med. 2022 Jun;26(12):3378-3386. doi: 10.1111/jcmm.17341. Epub 2022 May 2. PMID: 35502484; PMCID: PMC9189331. 4: Willette RN, Mangrolia P, Pondell SM, Lee CYW, Yoo S, Rudoltz MS, Cowen BR, Welsch DJ. Modulation of Oxidative Phosphorylation with IM156 Attenuates Mitochondrial Metabolic Reprogramming and Inhibits Pulmonary Fibrosis. J Pharmacol Exp Ther. 2021 Nov;379(3):290-300. doi: 10.1124/jpet.121.000811. Epub 2021 Sep 30. PMID: 34593558. 5: Izreig S, Gariepy A, Kaymak I, Bridges HR, Donayo AO, Bridon G, DeCamp LM, Kitchen-Goosen SM, Avizonis D, Sheldon RD, Laister RC, Minden MD, Johnson NA, Duchaine TF, Rudoltz MS, Yoo S, Pollak MN, Williams KS, Jones RG. Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment. Cell Rep Med. 2020 May 19;1(2):100014. doi: 10.1016/j.xcrm.2020.100014. PMID: 32478334; PMCID: PMC7249503. 6: Son J, Cho YW, Woo YJ, Baek YA, Kim EJ, Cho Y, Kim JY, Kim BS, Song JJ, Ha SJ. Metabolic Reprogramming by the Excessive AMPK Activation Exacerbates Antigen-Specific Memory CD8+ T Cell Differentiation after Acute Lymphocytic Choriomeningitis Virus Infection. Immune Netw. 2019 Mar 5;19(2):e11. doi: 10.4110/in.2019.19.e11. PMID: 31089438; PMCID: PMC6494768.