IACS-010759 HCl | IACS-10759 | CAS#1807523-99-4 | OXPHOS inhibitor

MedKoo Cat#: 206741 | Name: IACS-010759 HCl

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Description:

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

IACS-010759 or IACS-10759 is a potent inhibitor of complex I of OXPHOS. IACS-10759 effectively inhibits ATP production and oxygen consumption in isolated mitochondria, and inhibits the conversion of NADH to NAD+ in immunoprecipitated complex I in low nM range. IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species, and shows significant efficacy in multiple tumor indications both in vitro and in vivo. IACS-10759 causes robust tumor regression, but has no effect in the same model when glycolysis is restored.

Chemical Structure

IACS-010759 HCl

CAS#1807523-99-4 (HCl)

Theoretical Analysis

MedKoo Cat#: 206741

Name: IACS-010759 HCl

CAS#: 1807523-99-4 (HCl)

Chemical Formula: C25H26ClF3N6O4S

Exact Mass: 0.0000

Molecular Weight: 599.03

Elemental Analysis: C, 50.13; H, 4.38; Cl, 5.92; F, 9.51; N, 14.03; O, 10.68; S, 5.35

Price and Availability

Size	Price	Availability	Quantity
100mg	USD 1,250.00	2 Weeks
1g	USD 5,450.00	2 weeks

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Related CAS #

1807523-99-4 (HCl) 1570496-34-2 (free base) 1807524-00-0 (besylate) 1807524-01-1 (mesylate) 1807524-05-5 (tosylate)

Synonym

IACS-010759 HCl; IACS-010759 hydrochloride; IACS-10759; IACS 10759; IACS10759; IACS-010759; IACS 010759; IACS010759.

IUPAC/Chemical Name

5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole hydrochloride

InChi Key

LUSCFOVOISLXTM-UHFFFAOYSA-N

InChi Code

LUSCFOVOISLXTM-UHFFFAOYSA-N

SMILES Code

FC(F)(F)OC1=CC=C(C2=NOC(C3=NN(CC4=CC=CC(N5CCC(S(=O)(C)=O)CC5)=C4)C(C)=N3)=N2)C=C1.[H]Cl

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

>2 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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

IACS-010759 hydrochlorideis an orally active, potent mitochondrial complex I of oxidative phosphorylation (OXPHOS) inhibitor.

In vitro activity:

In contrast, IACS-010759 treatment led to a dose-dependent reduction in OCR (oxygen consumption rate) in all cell lines examined (Fig. 1d), irrespective of differences in MCT4 expression, their underlying molecular pathology, or categorisations related to COO or CCC status (Supplementary Fig. S1). Reference: Br J Cancer. 2022 Sep;127(5):937-947. https://pubmed.ncbi.nlm.nih.gov/35618788/

In vivo activity:

The citrate m+2/pyruvate m+3 ratio is used to indicate PDH-dependent labeling, while citrate m+3/pyruvate m+3 is used to indicate PC-dependent labeling. Both ratios declined upon treatment with IACS-010759 in every xenograft model examined except for M405 tumors (Fig. 3, K and L). Reference: Sci Adv. 2022 Sep 2;8(35):eabn9550. https://pubmed.ncbi.nlm.nih.gov/36044570/

	Solvent	mg/mL	mM
Solubility
	DMSO	60.0	50.08

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 599.03 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. Noble RA, Thomas H, Zhao Y, Herendi L, Howarth R, Dragoni I, Keun HC, Vellano CP, Marszalek JR, Wedge SR. 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. 2. Baran N, Lodi A, Dhungana Y, Herbrich S, Collins M, Sweeney S, Pandey R, Skwarska A, Patel S, Tremblay M, Kuruvilla VM, Cavazos A, Kaplan M, Warmoes MO, Veiga DT, Furudate K, Rojas-Sutterin S, Haman A, Gareau Y, Marinier A, Ma H, Harutyunyan K, Daher M, Garcia LM, Al-Atrash G, Piya S, Ruvolo V, Yang W, Shanmugavelandy SS, Feng N, Gay J, Du D, Yang JJ, Hoff FW, Kaminski M, Tomczak K, Eric Davis R, Herranz D, Ferrando A, Jabbour EJ, Emilia Di Francesco M, Teachey DT, Horton TM, Kornblau S, Rezvani K, Sauvageau G, Gagea M, Andreeff M, Takahashi K, Marszalek JR, Lorenzi PL, Yu J, Tiziani S, Hoang T, Konopleva M. Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia. Nat Commun. 2022 May 19;13(1):2801. doi: 10.1038/s41467-022-30396-3. PMID: 35589701; PMCID: PMC9120040. 3. Pachnis P, Wu Z, Faubert B, Tasdogan A, Gu W, Shelton S, Solmonson A, Rao AD, Kaushik AK, Rogers TJ, Ubellacker JM, LaVigne CA, Yang C, Ko B, Ramesh V, Sudderth J, Zacharias LG, Martin-Sandoval MS, Do D, Mathews TP, Zhao Z, Mishra P, Morrison SJ, DeBerardinis RJ. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors. Sci Adv. 2022 Sep 2;8(35):eabn9550. doi: 10.1126/sciadv.abn9550. Epub 2022 Aug 31. PMID: 36044570; PMCID: PMC9432826. 4. de Groot E, Varghese S, Tan L, Knighton B, Sobieski M, Nguyen N, Park YS, Powell R, Lorenzi PL, Zheng B, Stephan C, Gopal YNV. Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas. Cancer Metab. 2022 Feb 22;10(1):6. doi: 10.1186/s40170-022-00281-0. PMID: 35193687; PMCID: PMC8862475.

In vitro protocol:

In vivo protocol:

1. Pachnis P, Wu Z, Faubert B, Tasdogan A, Gu W, Shelton S, Solmonson A, Rao AD, Kaushik AK, Rogers TJ, Ubellacker JM, LaVigne CA, Yang C, Ko B, Ramesh V, Sudderth J, Zacharias LG, Martin-Sandoval MS, Do D, Mathews TP, Zhao Z, Mishra P, Morrison SJ, DeBerardinis RJ. In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors. Sci Adv. 2022 Sep 2;8(35):eabn9550. doi: 10.1126/sciadv.abn9550. Epub 2022 Aug 31. PMID: 36044570; PMCID: PMC9432826. 2. de Groot E, Varghese S, Tan L, Knighton B, Sobieski M, Nguyen N, Park YS, Powell R, Lorenzi PL, Zheng B, Stephan C, Gopal YNV. Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas. Cancer Metab. 2022 Feb 22;10(1):6. doi: 10.1186/s40170-022-00281-0. PMID: 35193687; PMCID: PMC8862475.

1: An OXPHOS Inhibitor Has Antitumor Activity in Multiple Tumor Models. Cancer Discov. 2018 Aug;8(8):OF13. doi: 10.1158/2159-8290.CD-RW2018-106. Epub 2018 Jun 22. PubMed PMID: 29934314. 2: Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, McAfoos T, Morlacchi P, Ackroyd J, Agip AA, Al-Atrash G, Asara J, Bardenhagen J, Carrillo CC, Carroll C, Chang E, Ciurea S, Cross JB, Czako B, Deem A, Daver N, de Groot JF, Dong JW, Feng N, Gao G, Gay J, Do MG, Greer J, Giuliani V, Han J, Han L, Henry VK, Hirst J, Huang S, Jiang Y, Kang Z, Khor T, Konoplev S, Lin YH, Liu G, Lodi A, Lofton T, Ma H, Mahendra M, Matre P, Mullinax R, Peoples M, Petrocchi A, Rodriguez-Canale J, Serreli R, Shi T, Smith M, Tabe Y, Theroff J, Tiziani S, Xu Q, Zhang Q, Muller F, DePinho RA, Toniatti C, Draetta GF, Heffernan TP, Konopleva M, Jones P, Di Francesco ME, Marszalek JR. 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. PubMed PMID: 29892070. 3: Lissanu Deribe Y, Sun Y, Terranova C, Khan F, Martinez-Ledesma J, Gay J, Gao G, Mullinax RA, Khor T, Feng N, Lin YH, Wu CC, Reyes C, Peng Q, Robinson F, Inoue A, Kochat V, Liu CG, Asara JM, Moran C, Muller F, Wang J, Fang B, Papadimitrakopoulou V, Wistuba II, Rai K, Marszalek J, Futreal PA. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat Med. 2018 Jul;24(7):1047-1057. doi: 10.1038/s41591-018-0019-5. Epub 2018 Jun 11. Erratum in: Nat Med. 2018 Aug 13;:. PubMed PMID: 29892061. 4: Vangapandu HV, Alston B, Morse J, Ayres ML, Wierda WG, Keating MJ, Marszalek JR, Gandhi V. 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. eCollection 2018 May 18. PubMed PMID: 29861847; PubMed Central PMCID: PMC5982765.