Solute carrier family 7 member 11 (SLC7A11, also known as xCT), the functional light chain subunit of the cystine/glutamate antiporter system xc⁻ [1]
HG106 specifically targets SLC7A11 (solute carrier family 7 member 11), also known as xCT, which is the cystine/glutamate antiporter. SLC7A11 is a transmembrane protein that mediates the exchange of extracellular cystine for intracellular glutamate, providing cells with cystine for glutathione biosynthesis. Glutathione is a critical intracellular antioxidant that protects cells from oxidative stress and is essential for cell survival under conditions of high ROS production. By inhibiting SLC7A11, HG106 blocks cystine uptake, depleting the intracellular cysteine pool and reducing glutathione synthesis. This leads to increased ROS levels and oxidative stress, which are particularly toxic to KRAS-mutant cancer cells that rely on glutathione for redox homeostasis. The compound's specificity for KRAS-mutant LUAD cells is a key feature that enables selective targeting of cancer cells while sparing normal cells.

HG106 inhibited ¹⁴C-cystine uptake in a concentration-dependent manner in KRAS-mutant LUAD cells, with the lowest effective concentration at 1.25 μmol/L. At 10 μmol/L, its efficacy was comparable to that of sulfasalazine at 1 mmol/L, indicating 100-fold greater activity. [1]
HG106 concentration-dependently inhibited glutathione production in KRAS-mutant LUAD cells, with the lowest effective concentration at 1.25 μmol/L. [1]
Metabolomic profiling showed that HG106 rewired multiple metabolic pathways, with glutathione biosynthesis ranked as the most significantly affected pathway. Levels of key metabolites in the glutathione metabolism pathway, including cystine, glutathione, and glycine, were suppressed. [1]
HG106 exerted substantial cytotoxic effects on KRAS-mutant H441 cells, which were strikingly reduced by addition of β-mercaptoethanol and L-cysteine. [1]
Genetic depletion of SLC7A11 significantly reduced the potency of HG106, suggesting its specificity toward SLC7A11. [1]
HG106 activated ERK but exhibited no obvious inhibitory actions on a panel of kinases, RAS activity, or other MAPK pathway components. [1]
HG106 dose-dependently increased total ROS levels in A549 cells. Treatment with the ROS scavenger N-acetylcysteine (NAC) markedly reduced the cytotoxicity of HG106. [1]
HG106 dose-dependently reduced the oxygen consumption rate and disrupted mitochondrial membrane potential (MMP) in A549 and H441 cells. [1]
Transmission electron microscopy revealed that cells treated with HG106 exhibited mitochondrial swelling, similar to the effects of hydrogen peroxide. [1]
HG106 increased the activation of ER stress-related markers IRE1α, PERK, and GRP78, as well as the transcription of CHOP, ATF4, and ATF6. [1]
HG106 significantly induced apoptosis in KRAS-mutant LUAD cells and inhibited colony formation. [1]
HG106 selectively killed KRAS-mutant cancer cells compared with KRAS WT cells across a panel of cancer cell lines. Normal cells were less affected by HG106 when compared with KRAS-mutant cells. [1]
HG106 treatment did not lead to autophagy-related cell death or ferroptosis. [1]

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In vitro, HG106 potently inhibits SLC7A11-mediated cystine uptake, markedly decreasing intracellular cystine levels and glutathione biosynthesis. This inhibition leads to enhanced reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress, ultimately causing growth arrest specifically in KRAS-mutant lung adenocarcinoma (LUAD) cells. The compound exhibits selectivity for KRAS-mutant cancer cells over normal cells or cancer cells with wild-type KRAS, reflecting the heightened dependence of KRAS-mutant cells on SLC7A11-mediated glutathione synthesis for survival under oxidative stress. The compound's anti-inflammatory properties have also been noted, and it may be used to study diseases caused by RAS gene mutations. In vitro studies have demonstrated that HG106 induces apoptosis through increased oxidative and ER stress.

In an A549 xenograft mouse model, continuous HG106 treatment (daily intraperitoneal injection) led to prolonged tumor growth inhibition at tested doses. [1]
In a patient-derived xenograft (PDX) model of LUAD harboring a G12V mutation in KRAS, HG106 strikingly suppressed PDX tumor growth after 3 weeks of treatment. [1]
In LSL-KrasG12D mice, lung tumor volume (assessed by microCT imaging) was significantly reduced by HG106. The median survival in infected LSL-KrasG12D vehicle mice was 39 days, whereas it was prolonged to 81 or 106 days in two HG106-treated groups, respectively. [1]
In LSL-KrasG12D/Trp53⁺/⁻ (KP) mice, HG106 treatment led to significant tumor inhibition compared with the vehicle group (P < 0.001) and produced a higher long-term survival advantage (log-rank test; P = 0.0048). [1]
HG106 at doses of 2 or 4 mg/kg markedly increased ROS production and TUNEL signal in patient-derived xenografts, validating that HG106 triggered ER stress-induced apoptosis in vivo. [1]

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In vivo, HG106 has been investigated in preclinical models of KRAS-mutant lung adenocarcinoma. By inhibiting SLC7A11, the compound decreases cystine uptake and glutathione biosynthesis, leading to enhanced ROS generation, ER stress, and tumor growth inhibition in KRAS-mutant LUAD. The compound's selective activity against KRAS-mutant cancer cells makes it a promising tool for studying the therapeutic potential of targeting the SLC7A11/glutathione axis in RAS-mutant cancers. Specific in vivo efficacy data, including tumor growth inhibition rates and survival benefits, has been reported in the primary literature describing the compound. HG106 has been evaluated in mouse models of KRAS-mutant lung adenocarcinoma.

¹⁴C-cystine uptake assay: Cells were plated at 100,000 cells per well in 12-well plates. After overnight adherence, cells were treated with HG106 (1.25, 2.5, 5, 10 μM) for 3 minutes. Cells were then washed with PBS and incubated in prewarmed Na⁺-free buffer at 37°C for 10 minutes. L-[3,3′-¹⁴C]-cystine (0.2 μCi/mL) was added for 15 minutes. Cells were lysed with 200 μL of 0.1 M NaOH solution, and scintillation fluid was added. Radioactive [¹⁴C] counts per minute were obtained using a liquid scintillation counter. [1]
Glutathione detection: Cells were plated in 6-well plates at a density of 800,000–1,000,000 cells per well. Cells were treated with HG106 (1.25, 2.5, 5, 10 μM) for 12 hours. Glutathione levels were evaluated using a GSH/GSSG-Glo assay kit following the manufacturer's instructions. Glutathione concentration was calculated from an internal standard curve and normalized to total cell number. [1]
ROS evaluation: Cells were treated with HG106 (2.5, 5, 10 μM) for 6 hours in 6-well plates at a density of 300,000–500,000 cells per well. Cells were harvested in conditioned DMEM containing DCFH-DA (25 μM). After incubation at 37°C for 30 minutes, cells were washed with PBS and subjected to flow cytometry. [1]
Mitochondrial oxygen consumption rate (OCR) measurement: OCR values were normalized to sulforhodamine staining. [1]
Mitochondrial membrane potential (MMP) measurement: MMP change in HG106-treated A549 cells was measured using CCCP (carbonyl cyanide 3-chlorophenylhydrazone) as a control. [1]

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The inhibitory activity of HG106 against SLC7A11 is assessed using cystine uptake assays. Cells are incubated with radiolabeled or fluorescently labeled cystine in the presence of varying concentrations of the compound, and the amount of cystine taken up by cells is quantified. Intracellular glutathione levels are measured using colorimetric, fluorometric, or LC-MS-based assays. Reactive oxygen species (ROS) levels are assessed using fluorescent probes such as DCFH-DA or CellROX. Endoplasmic reticulum (ER) stress markers such as CHOP, BIP, and phosphorylated eIF2α are measured by Western blotting or qRT-PCR. Cell viability and proliferation are assessed using MTT, CCK-8, or CellTiter-Glo assays.

Cell viability assay: KRAS isogenic cells and a panel of KRAS mutant (n = 18) and WT KRAS (n = 8) cancer cell lines were treated with HG106 for 72 hours. Cell viability was measured, and IC50 values were calculated. [1]
Colony formation assay: A549 cells were plated in 6-well plates and treated with the indicated concentrations of HG106 for 7 days. The relative number of colonies was calculated by normalization to the untreated group as 100%. Scale bar: 0.5 cm. [1]
Apoptosis assay: A549 cell apoptosis induced by HG106 was measured. [1]
Calcein-AM staining: Cell survival was determined by calcein-AM staining (green, viable cells). Scale bar: 50 μm. [1]
Transmission electron microscopy: Mitochondria morphology was examined. Red arrowheads indicate swelling of mitochondria. Scale bar: 0.5 μm. [1]
Western blotting: A549 cells were treated with HG106 and sulfasalazine (1 mM) for 24 hours. Immunoblots were contemporaneous and run in parallel from the same biological replicate for ER stress-related markers (IRE1α, PERK, GRP78). [1]
RT-qPCR: Transcription of CHOP, ATF4, and ATF6 was measured. [1]

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Cellular assays for HG106 are performed using KRAS-mutant lung adenocarcinoma cell lines (such as H358, H23, A549) and control cell lines with wild-type KRAS. Cells are cultured in appropriate growth medium and treated with varying concentrations of HG106 for specified time periods (typically 24-72 hours). Cell viability is measured using standard colorimetric or luminescent assays. Cystine uptake is measured using radiolabeled or fluorescent cystine tracers. Intracellular glutathione levels are quantified using enzymatic recycling assays or LC-MS. ROS levels are measured using fluorescent probes. Apoptosis is assessed using annexin V/PI staining or caspase activity assays. The compound is soluble in DMSO at 20-26 mg/mL.

A549 xenograft model: 6-week-old BALB/cA nude mice were injected subcutaneously with A549 cells (5 × 10⁶). When tumors reached a volume of approximately 150 mm³, mice were treated with vehicle chow or different dosages of HG106 through daily intraperitoneal injection. HG106 was dissolved in 0.5% sodium carboxymethylcellulose (CMC-Na). Mice intraperitoneally injected with 0.5% CMC-Na served as the vehicle control. Tumor volumes were measured every other day, and mouse body weight was recorded in parallel. After the last day of treatment, tumors were excised and weighed. [1]
Patient-derived xenograft (PDX) model: Fragments from a poorly differentiated LUAD harboring a KRAS(G12V) mutation were implanted subcutaneously into mice. After inoculation, mice were monitored until tumor volumes grew to 100–200 mm³. Mice were randomized into 4 groups and treated with vehicle or different dosages of HG106 for about 1 month. HG106 was dissolved in 0.5% CMC-Na and delivered daily by intraperitoneal injections. [1]
LSL-KrasG12D mouse model: 8-week-old LSL-KrasG12D mice were anesthetized with isoflurane. Adeno-Cre at a dose of 2.5 × 10⁷ PFU in a total volume of 125 μL was introduced intratracheally. Five weeks after virus inhalation, lungs were imaged by microCT to confirm tumor formation. After tumor formation, animals were randomized into two groups treated with HG106 at a dosage of 4 mg/kg/d. HG106 was dissolved in 0.5% CMC-Na and delivered daily by intraperitoneal injections. [1]
LSL-KrasG12D/Trp53⁺/⁻ (KP) mouse model: 8-week-old KP mice were anesthetized with isoflurane. Adeno-Cre at a dose of 2.5 × 10⁷ PFU in a total volume of 125 μL was introduced intratracheally. Five weeks after virus inhalation, lungs were imaged by microCT to confirm tumor formation. After tumor formation, animals were randomized into two groups treated with HG106 at a dosage of 4 mg/kg/d. HG106 was dissolved in 0.5% CMC-Na and delivered daily by intraperitoneal injections. [1]

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In vivo studies of HG106 are conducted in mouse xenograft models of KRAS-mutant lung adenocarcinoma. Tumor-bearing mice are administered the compound via intraperitoneal (i.p.) injection or oral gavage. For oral administration, the compound can be formulated as a homogeneous suspension in CMC-Na at concentrations ≥5 mg/mL. For injection, the compound can be formulated in 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% ddH2O at 0.5 mg/mL. Tumor volumes are measured at regular intervals using calipers. Pharmacodynamic markers including glutathione levels, ROS levels, and ER stress markers are assessed in tumor tissues. Body weight and overall health are monitored for tolerability.

Pharmacokinetic properties of HG106 (molecular weight 316.74, molecular formula C15H13ClN4O2) have been characterized. The compound is soluble in DMSO at 20-26 mg/mL and is insoluble in water and ethanol. For in vivo oral administration, HG106 can be formulated as a homogeneous suspension in CMC-Na at concentrations ≥5 mg/mL. For intravenous or intraperitoneal injection, the compound can be formulated in 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% ddH2O at 0.5 mg/mL. Storage recommendations include powder storage under appropriate conditions. Comprehensive PK parameters including oral bioavailability, half-life, and volume of distribution are available from the primary literature describing the compound.

Normal cells were less affected by HG106 when compared with KRAS-mutant cells, indicating the safety and low toxicity of HG106. [1]

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HG106 is intended for research use only and is not approved for human therapeutic applications. Comprehensive toxicological evaluations have been conducted in preclinical studies. The compound's mechanism of action—inhibiting SLC7A11 and depleting glutathione—leads to increased oxidative stress and ER stress, which can be toxic to cells. This on-target activity is responsible for the compound's anticancer effects but also necessitates careful evaluation of potential toxicity to normal tissues. Standard safety pharmacology assessments would be required if the compound were to be considered for therapeutic development.

[1]. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J Clin Invest. 2020 Apr 1;130(4):1752-1766.

HG106 is a potent SLC7A11 inhibitor identified through a function-based chemical screen of a commercial library. The primary screening was carried out based on compounds' inhibitory effects on glutathione production in A549 cells. Hits were those with Z scores lower than -3. Most effective compounds belonged to a series of chemicals with a benzotriazole scaffold. HG106 exhibited the greatest potency and efficacy among synthesized derivatives. [1]
HG106 selectively kills KRAS-mutant LUAD cells by increasing oxidative stress- and ER stress-mediated cell apoptosis. SLC7A11 inhibition by HG106 leads to increased ROS generation, ER stress, mitochondrial dysfunction, and ultimately growth arrest specifically in KRAS-mutant LUAD. [1]
The synthetic lethal link between KRAS mutational status and a requirement for SLC7A11 function enables promising therapeutic approaches for the treatment of KRAS-mutant cancers. [1]

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HG106 is a research-grade compound used as a pharmacological tool for studying the SLC7A11/glutathione axis in cancer metabolism and ferroptosis. SLC7A11 is the cystine/glutamate antiporter that plays a critical role in maintaining intracellular glutathione levels and protecting cells from oxidative stress. KRAS-mutant cancer cells are particularly dependent on SLC7A11-mediated glutathione synthesis for survival, making SLC7A11 a promising synthetic lethal target for KRAS-mutant cancers. HG106 has been used to demonstrate that suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. The compound is available with purity ≥98-99%.

C15H13CLN4O2

316.74

316.07

C, 56.88; H, 4.14; Cl, 11.19; N, 17.69; O, 10.10

928712-10-1

16495618

Off-white to light yellow solid powder

2.8

1

4

4

22

390

0

C(NC1C=CC2=NN(C3=CC=C(OC)C=C3)N=C2C=1)(=O)CCl

YKONCCSKKBLMDS-UHFFFAOYSA-N

InChI=1S/C15H13ClN4O2/c1-22-12-5-3-11(4-6-12)20-18-13-7-2-10(8-14(13)19-20)17-15(21)9-16/h2-8H,9H2,1H3,(H,17,21)

2-chloro-N-[2-(4-methoxyphenyl)benzotriazol-5-yl]acetamide

HG106; 928712-10-1; 928712-10-1; 2-chloro-N-[2-(4-methoxyphenyl)-2H-1,2,3-benzotriazol-5-yl]acetamide; 2-chloro-N-(2-(4-methoxyphenyl)-2H-1,2,3-benzotriazol-5-yl)acetamide; RefChem:469998; ...; HG-106; EN300-27696107; Z3219837442

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : ~125 mg/mL (~394.65 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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