| Size | Price | Stock | Qty |
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| 50mg |
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| 100mg |
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| 500mg |
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| Targets |
Solute carrier family 7 member 11 (SLC7A11, also known as xCT), the functional light chain subunit of the cystine/glutamate antiporter system xc⁻ [1]
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| ln Vitro |
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] |
| ln Vivo |
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] |
| Enzyme Assay |
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] |
| Cell Assay |
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] |
| Animal Protocol |
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] |
| Toxicity/Toxicokinetics |
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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| References |
[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.
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| Additional Infomation |
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] |
| Molecular Formula |
C15H13CLN4O2
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|---|---|
| Molecular Weight |
316.74
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| Exact Mass |
316.07
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| Elemental Analysis |
C, 56.88; H, 4.14; Cl, 11.19; N, 17.69; O, 10.10
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| CAS # |
928712-10-1
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| PubChem CID |
16495618
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
22
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| Complexity |
390
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(NC1C=CC2=NN(C3=CC=C(OC)C=C3)N=C2C=1)(=O)CCl
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| InChi Key |
YKONCCSKKBLMDS-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
2-chloro-N-[2-(4-methoxyphenyl)benzotriazol-5-yl]acetamide
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| Synonyms |
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
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| HS Tariff Code |
2934.99.9001
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| Storage |
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. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~394.65 mM)
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1572 mL | 15.7858 mL | 31.5716 mL | |
| 5 mM | 0.6314 mL | 3.1572 mL | 6.3143 mL | |
| 10 mM | 0.3157 mL | 1.5786 mL | 3.1572 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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