IACS-010759 free base
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MedKoo CAT#: 407917

CAS#: 1570496-34-2 (free base)

Description: IACS-010759 or IACS-10759 is a potent and selective Oxidative Phosphorylation Inhibitor (IC50 < 10 nM) with potential antineoplastic activity. IACS-010759 binds to and inhibits complex I of the electron transport chain (NADH ubiquinone oxidoreductase), thereby selectively depriving tumor cells of nutrients, and energy, and inhibiting nucleotide and amino acid production, which induces autophagy, causes tumor cell death and inhibits cell proliferation. Mitochondrial complex I, which is hyperactivated in cancer cells to meet their increased demands for energy, plays a key role in the promotion of cancer cell proliferation.


Chemical Structure

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IACS-010759 free base
CAS# 1570496-34-2 (free base)

Theoretical Analysis

MedKoo Cat#: 407917
Name: IACS-010759 free base
CAS#: 1570496-34-2 (free base)
Chemical Formula: C25H25F3N6O4S
Exact Mass: 562.161
Molecular Weight: 562.5682
Elemental Analysis: C, 53.38; H, 4.48; F, 10.13; N, 14.94; O, 11.38; S, 5.70

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1350.0 Ready to ship
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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; IACS 010759; IACS010759; IACS-10759; IACS 10759; IACS10759.

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

InChi Key: HWJWNWZJUYCGKV-UHFFFAOYSA-N

InChi Code: InChI=1S/C25H25F3N6O4S/c1-16-29-23(24-30-22(32-38-24)18-6-8-20(9-7-18)37-25(26,27)28)31-34(16)15-17-4-3-5-19(14-17)33-12-10-21(11-13-33)39(2,35)36/h3-9,14,21H,10-13,15H2,1-2H3

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

Appearance: White to off-white 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

Biological target: IACS-010759 (IACS-10759) is an inhibitor of complex I of oxidative phosphorylation (OXPHOS) with IC50 < 10 nM.
In vitro activity: CLL (chronic lymphocytic leeukemia) cells were incubated with 100 nM IACS-010759 for 24 h and later assayed for changes in mitochondrial OCR (oxygen consumption rate, a measure of OxPhos) and ECAR (a measure of glycolysis). Untreated cells showed the expected increase in spare respiratory capacity upon addition of uncoupler carbonylcyanide-4-trifluoromethoxyphenylhydrazone (FCCP). In drug-treated cells, basal OCR was greatly inhibited followed by a drastic decrease in spare respiratory capacity (after addition of FCCP) compared with the untreated control (Figure 2A). Similar assays were done in 10 patient samples where basal respiratory capacity (Figure 2B) and spare respiratory capacity showed a similar trend after incubation with the drug (Figure 2C). Glycolysis was measured simultaneously in these patient samples. An increase in glycolytic flux was observed in treated cells compared with untreated cells (Figure 2D). A similar increase in glycolytic flux was noted when an additional 11 samples were evaluated (Figure 2E). Because glycolytic flux increased, glucose consumption by the cells (substrate for glycolysis) was measured. 2-dG was used to measure glucose uptake in untreated and after a 24 h treatment with IACS-010759 (Figure 2F). Glucose uptake was significantly increased after treatment. Reference: Oncotarget. 2018 May 18;9(38):24980-24991. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982765/
In vivo activity: IACS-010759 is a mitochondrial complex I inhibitor that has demonstrated preclinical antileukemic activity. However, complex I deficiency has been reported to inhibit apoptotic cell death through prevention of cytochrome c release. Thus, combining IACS-010759 with a BH3 mimetic may overcome this mechanism of resistance leading to synergistic antileukemic activity against AML (acute myeloid leukemia). In a relatively OXPHOS-reliant AML cell line derived xenograft mouse model, IACS-010759 treatment significantly prolonged survival, which was further enhanced by treatment with IACS-010759 in combination with venetoclax. IACS-010759 treatment retained cytochrome c in mitochondria, which was completely abolished by venetoclax, resulting in Bak/Bax- and caspase-dependent apoptosis. Reference: Cancers (Basel). 2020 Aug 24;12(9):2400. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564145/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 24.23 43.07
DMF 0.1 0.18

Preparing Stock Solutions

The following data is based on the product molecular weight 562.5682 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.

Recalculate based on batch purity %
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. 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. PMID: 29861847; PMCID: PMC5982765. 2. Liu F, Kalpage HA, Wang D, Edwards H, Hüttemann M, Ma J, Su Y, Carter J, Li X, Polin L, Kushner J, Dzinic SH, White K, Wang G, Taub JW, Ge Y. Cotargeting of Mitochondrial Complex I and Bcl-2 Shows Antileukemic Activity against Acute Myeloid Leukemia Cells Reliant on Oxidative Phosphorylation. Cancers (Basel). 2020 Aug 24;12(9):2400. doi: 10.3390/cancers12092400. PMID: 32847115; PMCID: PMC7564145. 3. 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. PMID: 29892070.
In vitro protocol: 1. 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. PMID: 29861847; PMCID: PMC5982765. 2. Liu F, Kalpage HA, Wang D, Edwards H, Hüttemann M, Ma J, Su Y, Carter J, Li X, Polin L, Kushner J, Dzinic SH, White K, Wang G, Taub JW, Ge Y. Cotargeting of Mitochondrial Complex I and Bcl-2 Shows Antileukemic Activity against Acute Myeloid Leukemia Cells Reliant on Oxidative Phosphorylation. Cancers (Basel). 2020 Aug 24;12(9):2400. doi: 10.3390/cancers12092400. PMID: 32847115; PMCID: PMC7564145.
In vivo protocol: 1. 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. PMID: 29892070. 2. Liu F, Kalpage HA, Wang D, Edwards H, Hüttemann M, Ma J, Su Y, Carter J, Li X, Polin L, Kushner J, Dzinic SH, White K, Wang G, Taub JW, Ge Y. Cotargeting of Mitochondrial Complex I and Bcl-2 Shows Antileukemic Activity against Acute Myeloid Leukemia Cells Reliant on Oxidative Phosphorylation. Cancers (Basel). 2020 Aug 24;12(9):2400. doi: 10.3390/cancers12092400. PMID: 32847115; PMCID: PMC7564145.

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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.



Additional Information

http://mct.aacrjournals.org/content/14/12_Supplement_2/LB-A15