IC50: 3.65 μM (HIF-1α)
Hypoxia-inducible factor-1α (HIF-1α) (IC₅₀ = 3.65 µM in HRE-luciferase reporter assay in HCT116 cells) [1]
HSP70 chaperone activity (allosteric inhibitor) [1]

In cancer cell lines, IDF-11774 is a new inhibitor of hypoxia-inducible factor (HIF)-1, having an IC50 of 3.65 μM. A Phase I study has approved IDF-11774 as a therapeutic medication candidate. IDF-11774 treatment of human umbilical cord vascular endothelial cells (HUVEC) resulted in less capillary network development on Matrigel. Treatment with IDF-11774 led to a reduction in GLUT1 and pyruvate dehydrogenase kinase 1 (PDK1) mRNA expression. Moreover, intracellular ATP levels were considerably lowered when IDF-11774 was present, and the effects were more pronounced when low glucose levels (5.5 mM) were present [1].

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IDF-11774 inhibited HIF-1α accumulation under hypoxic conditions in HCT116 human colon cancer cells [1]
IDF-11774 treatment for 18 hours under hypoxia reduced mRNA expression of the HIF-1 target genes VEGF and EPO, but not HIF-1α itself, in HCT116 cells [1]
In an in vitro tube formation assay using human umbilical vascular endothelial cells (HUVECs), IDF-11774 treatment reduced capillary network formation on Matrigel under 1% O₂, similar to the positive control sunitinib [1]
This inhibition of tube formation by IDF-11774 was rescued by the addition of VEGF [1]
IDF-11774 treatment for 6 hours under hypoxia reduced mRNA expression of the HIF-1 target genes GLUT1 and PDK1 in HCT116 cells [1]
IDF-11774 markedly suppressed the cellular uptake of 2-deoxyglucose (2DG) in HCT116 cells [1]
Intracellular ATP levels were significantly reduced in HCT116 cells treated with IDF-11774 for 12 hours, with a greater effect under low glucose (5.5 mM) conditions [1]
IDF-11774 treatment for 72 hours caused stronger growth inhibition in HCT116 cells cultured in low glucose medium (5.5 mM) compared to high glucose medium (25 mM) [1]
IDF-11774 inhibited both basal and oligomycin-mediated extracellular acidification rate (ECAR), an indicator of glycolysis, in HCT116 cells in a dose-dependent manner [1]
IDF-11774 significantly inhibited the oxygen consumption rate (OCR), an indicator of mitochondrial respiration, in HCT116 cells in a concentration-dependent manner [1]
Metabolic profiling via ¹H-NMR spectroscopy of HCT116 cells treated with 10 µM IDF-11774 for 12 hours under hypoxia showed significant reductions in the levels of many glycolysis and TCA cycle metabolites, including lactate, NAD⁺, NADP⁺, fumarate, malate, and succinate [1]
The same treatment increased cellular AMP levels and decreased ATP levels, resulting in an elevated AMP/ATP ratio [1]
Western blot analysis showed that IDF-11774 treatment increased phosphorylation of AMPK, inactivated ACC (reduced p-ACC), and suppressed phosphorylation of mTOR and 4EBP1 in HCT116 cells [1]
IDF-11774 inhibited HIF-1α accumulation and the growth of various cancer cell lines (A549, NCI-H1975, MIA-PaCa-2, PC-3, Caki-1, 786-O) [1]

When mice treated with oral IDF-11774 had tumors, luciferase activity and HIF-1α accumulation were significantly reduced in comparison to controls. Oral IDF-11774 treatment for two weeks resulted in significant dose-dependent tumor shrinkage in mice models [1].

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In an in vivo bioluminescence imaging assay using HCT116 cells expressing HRE-luciferase, oral administration of IDF-11774 (50 mg/kg) strongly suppressed luciferase activity and HIF-1α accumulation in tumors compared to the vehicle control [1]
In a chick embryo chorioallantoic membrane (CAM) assay, treatment with IDF-11774 (20 µg per egg) reduced vessel formation in vivo, similar to sunitinib (10 µg per egg) [1]
In HCT116 xenograft models, oral administration of IDF-11774 daily for two weeks induced significant dose-dependent tumor regression at 10, 30, and 60 mg/kg [1]
Combination therapy of oral IDF-11774 (30 mg/kg, q.d.) with oral sunitinib (30 mg/kg, q.d.) resulted in a significant increase in anticancer efficacy compared to each agent alone in an HCT116 xenograft model [1]
Combination of intravenous IDF-11774 (30 mg/kg, twice a week) with oral sunitinib (30 mg/kg, q.d.) also enhanced antitumor efficacy compared to each treatment alone [1]
Combination of oral IDF-11774 (60 mg/kg, q.d.) with oral sorafenib or lapatinib (30 mg/kg each, q.d.) showed enhanced anticancer efficacy in HCT116 xenograft models [1]
IDF-11774 exhibited significant tumor growth inhibition in various other xenograft models: A549 (KRAS mutant, 60 mg/kg p.o., 51% TGI), NCI-H1975 (EGFR T790M mutant, 50 mg/kg p.o., 32% TGI), MIA-PaCa-2 (pancreatic cancer, 60 mg/kg p.o., 48% TGI), PC-3 (PTEN-null, 60 mg/kg p.o., 62% TGI), Caki-1 (renal cancer, wild-type VHL, 60 mg/kg p.o., 34% TGI), and 786-O (renal cancer, truncated VHL, 100 mg/kg p.o., 62% TGI) [1]

The HRE-luciferase reporter assay was used to measure HIF-1 activity. HCT116 cells expressing a luciferase gene under the control of hypoxia response elements (HREs) were treated with IDF-11774. Luciferase activity was measured, and the IC₅₀ value for HIF-1α inhibition was calculated [1]

For Western blot analysis of HIF-1α and signaling proteins, cells were lysed with RIPA buffer containing protease and phosphatase inhibitors. Protein concentrations were quantified, and proteins were separated by SDS-PAGE, transferred to membranes, and detected using specific antibodies and an enhanced chemiluminescence kit [1]
For quantitative real-time PCR analysis of gene expression, total RNA was extracted from cells treated with IDF-11774. cDNA was synthesized and amplified using SYBR Green qPCR Mastermix and specific primers for target genes (VEGF, EPO, GLUT1, PDK1, HIF-1α). Data were analyzed using specialized software [1]
For the in vitro tube formation assay, HUVECs were seeded on Matrigel-coated plates and treated with IDF-11774 or controls under hypoxic conditions (1% O₂) for 24 hours. Tubule branches were observed and photographed under a microscope [1]
For glucose uptake measurement, HCT116 cells were incubated in Krebs-Ringer phosphate buffer with radiolabeled 2-deoxyglucose (2DG). Cellular uptake of 2DG was measured by liquid scintillation counting [1]
For measurement of glycolytic flux (ECAR) and mitochondrial respiration (OCR), HCT116 cells were seeded in specialized plates. Using an extracellular flux analyzer, the ECAR was measured under basal conditions and after sequential injection of glucose and oligomycin. The OCR was measured under basal conditions and after sequential injection of oligomycin, FCCP, and rotenone/antimycin A, following the manufacturer's instructions [1]
For metabolic profiling via ¹H-NMR, polar metabolites were extracted from cells treated with IDF-11774 using a solvent mixture of methanol, water, and chloroform. ¹H-NMR spectra were acquired on a high-field NMR spectrometer. Metabolites were identified and quantified using specialized software and a spectral library [1]

For xenograft studies, cancer cells (e.g., HCT116, A549) were injected subcutaneously into 4- to 6-week-old female Balb/c nude mice [1]
When tumors reached approximately 100 mm³, mice were randomized into treatment groups [1]
IDF-11774 was administered either orally (per oral, p.o.) or intravenously (i.v.) [1]
For oral monotherapy studies, IDF-11774 was given once daily (q.d.) at doses of 10, 30, or 60 mg/kg for 15 days [1]
For combination therapy studies, IDF-11774 was given orally (30 or 60 mg/kg, q.d.) or intravenously (30 mg/kg, twice weekly) alongside other agents (sunitinib, sorafenib, lapatinib) administered orally (30 mg/kg, q.d.) [1]
Tumor volumes were measured regularly using calipers and calculated using the formula: Volume = (length × width × height) × 0.5 [1]
Body weight was monitored [1]

In xenotransplantation studies, no significant weight loss or side effects (such as skin ulcers or other serious symptoms) were observed in mice treated with IDF-11774 alone or in combination with other drugs [1].

[1]. The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. Cell Death Dis. 2017 Jun 1;8(6):e2843.

IDF-11774 is a novel oral HIF-1α inhibitor that has been approved by the Korean Food and Drug Administration for Phase I clinical trials[1].
It is developed based on the aryloxyacetaminobenzoic acid backbone[1].
Its mechanism of action is believed to bind to the allosteric pocket of HSP70, inhibiting its molecular chaperone activity, thereby inhibiting the refolding and accumulation of HIF-1α[1].
It can also reduce glucose uptake, inhibit glycolysis and mitochondrial respiration, leading to metabolic disorders (reduction of TCA cycle intermediates, NAD⁺, NADP⁺, and ATP) and activate the AMPK signaling pathway, thereby further attenuating HIF-1α translation by inhibiting mTOR[1].
It has shown efficacy in xenograft models carrying mutations associated with treatment resistance (KRAS, PTEN, EGFR T790M, VHL)[1].

C23H32N2O2

368.512386322021

368.246

1429054-28-3

71542096

White to off-white solid powder

4.6

0

3

4

27

505

0

O(CC(N1CCN(C)CC1)=O)C1C=CC(=CC=1)C12CC3CC(CC(C3)C1)C2

QGBBBLPWBSWERZ-KIOFGVERSA-N

InChI=1S/C23H32N2O2/c1-24-6-8-25(9-7-24)22(26)16-27-21-4-2-20(3-5-21)23-13-17-10-18(14-23)12-19(11-17)15-23/h2-5,17-19H,6-16H2,1H3/t17-,18-,19-,23?

2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one

IDF11774; IDF 11774; IDF-11774

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~60 mg/mL (~162.82 mM)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.67 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)