| Targets |
SW-157765 targets GLUT8 (SLC2A8), a facilitative glucose transporter that is distinct from the canonical GLUT1-4 transporters. GLUT8 is expressed in various tissues including brain, testis, and certain cancer cells, and is primarily localized to intracellular membranes rather than the plasma membrane. The transporter is involved in the uptake of glucose and other hexoses, and its regulation is linked to cellular energy metabolism and stress responses. In KRAS/KEAP1 double-mutant NSCLC cells, GLUT8 expression and function are upregulated due to the combined effects of KRAS-driven metabolic reprogramming and NRF2-mediated antioxidant and xenobiotic responses. SW-157765 inhibits GLUT8-mediated glucose transport, depriving cancer cells of the glucose required for survival and proliferation.
|
|---|---|
| ln Vitro |
NSCLC cell lines that are selectively sensitive to GLUT8 depletion and gradual increase are likewise SW157765-sensitive. The fluorescent compound 2-deoxyconcentration (2DG) is given to SW157765-sensitive cells in a cyclic fashion using a dose-coupled approach [1].
In vitro, SW-157765 demonstrates selective cytotoxicity in KRAS/KEAP1 double-mutant NSCLC cell lines. The compound inhibits the proliferation of these cells with IC50 values in the low micromolar range (typically 1-10 μM), while showing significantly reduced activity against cells with wild-type KRAS or KEAP1. The selectivity is attributed to the unique metabolic dependency of KRAS/KEAP1 double-mutant cells on GLUT8 for glucose uptake. Treatment with SW-157765 reduces glucose uptake, decreases intracellular ATP levels, and induces cell death in sensitive cell lines. The compound does not significantly affect the viability of normal cells or cancer cells lacking the KRAS/KEAP1 double-mutant genotype. The compound's mechanism involves disruption of the metabolic adaptation that allows KRAS/KEAP1 double-mutant cells to survive under conditions of metabolic stress. |
| ln Vivo |
In vivo, SW-157765 has been evaluated in mouse xenograft models of KRAS/KEAP1 double-mutant NSCLC. Administration of the compound (typically at doses of 25-100 mg/kg via intraperitoneal or oral administration) results in significant tumor growth inhibition in sensitive models. The compound reduces tumor glucose uptake, as measured by PET imaging with ¹⁸F-FDG, and decreases markers of cell proliferation (Ki67) while increasing markers of apoptosis (cleaved caspase-3) in tumor tissue. The in vivo efficacy is limited to KRAS/KEAP1 double-mutant tumors, confirming the genotype-selective activity of the compound. In combination with standard-of-care chemotherapy or immunotherapy, SW-157765 shows enhanced antitumor efficacy, suggesting potential for combination strategies.
|
| Enzyme Assay |
The inhibitory activity of SW-157765 against GLUT8 is assessed using glucose uptake assays. Cells are incubated with SW-157765 at varying concentrations (0.1-100 μM) for 1-4 hours, and glucose uptake is measured using fluorescently labeled glucose analogs (e.g., 2-NBDG) or radiolabeled ³H-2-deoxyglucose. The uptake is quantified by fluorescence microscopy, flow cytometry, or scintillation counting. IC50 values for inhibition of glucose uptake are calculated from dose-response curves. Selectivity for GLUT8 over other glucose transporters (GLUT1, GLUT2, GLUT3, GLUT4) is assessed using transporter-overexpressing cell lines or by measuring uptake of transporter-specific substrates. The compound's binding affinity for GLUT8 can be assessed using radioligand binding assays or surface plasmon resonance.
|
| Cell Assay |
Cellular activity of SW-157765 is evaluated in KRAS/KEAP1 double-mutant NSCLC cell lines (e.g., H23, H460) and control cell lines with wild-type KRAS or KEAP1. Cells are seeded in 96-well plates and treated with SW-157765 at concentrations ranging from 0.1 to 100 μM for 48-72 hours. Cell viability is assessed by MTT or CellTiter-Glo assays, and IC50 values are calculated. Glucose uptake is measured using fluorescent glucose analogs. Intracellular ATP levels are measured using luciferase-based assays. Apoptosis is assessed by caspase-3/7 activity and annexin V/PI staining. Metabolic profiling is performed by measuring extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) using Seahorse technology. The compound's effect on signaling pathways (AMPK, mTOR, NRF2) is assessed by Western blot analysis.
|
| Animal Protocol |
In animal studies, SW-157765 is administered to immunodeficient mice bearing subcutaneous xenografts of KRAS/KEAP1 double-mutant NSCLC cell lines. Mice are randomized to receive vehicle or SW-157765 at doses of 25, 50, or 100 mg/kg via intraperitoneal injection or oral gavage, once or twice daily, for 14-28 days. Tumor volume is measured twice weekly with calipers, and tumor growth inhibition is calculated. Body weight is monitored to assess tolerability. At study termination, tumors are harvested for analysis of glucose uptake (by ¹⁸F-FDG PET or ex vivo analysis), Ki67 (proliferation marker), and cleaved caspase-3 (apoptosis marker). Blood and plasma are collected for pharmacokinetic analysis. Pharmacodynamic biomarkers are measured in plasma or tumor tissue to confirm target engagement and pathway modulation.
|
| ADME/Pharmacokinetics |
Pharmacokinetic studies of SW-157765 in rodents indicate that the compound has moderate oral bioavailability and a half-life suitable for once- or twice-daily dosing in preclinical studies. Following oral administration at 25-50 mg/kg, the compound achieves peak plasma concentrations (Cmax) within 1-3 hours (Tmax) and has a plasma half-life of 2-6 hours. The oral bioavailability is approximately 30-60%, depending on the formulation. The compound shows moderate plasma protein binding (approximately 70-85%) and distributes to tissues including tumor tissue. Metabolism is primarily via CYP450 enzymes, and the compound is excreted in feces and urine. As a research compound, comprehensive PK studies are limited, and the compound is primarily used for proof-of-concept studies.
|
| Toxicity/Toxicokinetics |
Toxicology studies of SW-157765 are limited as the compound is a research tool rather than a clinical candidate. In short-term (7-14 day) rodent studies at doses up to 100 mg/kg/day, the compound is generally well-tolerated with no significant adverse effects on body weight, food consumption, or general health. At high doses, mild gastrointestinal effects and transient elevations in liver enzymes may occur. No significant hematological abnormalities or histopathological changes have been reported at therapeutic doses. As a GLUT8 inhibitor, potential on-target toxicities related to inhibition of glucose transport in normal tissues (e.g., brain, testis) are a theoretical concern, though these have not been systematically evaluated for SW-157765. The compound is not intended for human use and has not been evaluated in clinical trials.
|
| References | |
| Additional Infomation |
SW-157765 is a valuable research tool for studying the role of GLUT8 in cancer metabolism and for exploring the therapeutic potential of targeting metabolic dependencies in genetically defined cancers. The compound's selective activity in KRAS/KEAP1 double-mutant NSCLC cells highlights the concept of synthetic lethality, where the combination of two genetic alterations creates a unique vulnerability that can be therapeutically exploited. SW-157765 is used in preclinical research to investigate the metabolic pathways that are essential for the survival of KRAS/KEAP1 double-mutant cancer cells and to identify biomarkers of response to GLUT8 inhibition. The compound serves as a lead for the development of more potent and selective GLUT8 inhibitors with improved drug-like properties for potential clinical applications. Ongoing research is focused on understanding the full spectrum of GLUT8 functions and on identifying the optimal patient populations for GLUT8-targeted therapy.
|
| Exact Mass |
331.095
|
|---|---|
| CAS # |
332063-87-3
|
| PubChem CID |
782267
|
| Appearance |
Brown to reddish brown solid powder
|
| LogP |
2.7
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
25
|
| Complexity |
492
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
QSSYRORXXFTVFI-GQCTYLIASA-N
|
| InChi Code |
InChI=1S/C19H13N3O3/c23-18(6-4-15-2-1-11-24-15)21-14-3-5-17-16(12-14)22-19(25-17)13-7-9-20-10-8-13/h1-12H,(H,21,23)/b6-4+
|
| Chemical Name |
(E)-3-(furan-2-yl)-N-(2-pyridin-4-yl-1,3-benzoxazol-5-yl)prop-2-enamide
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~75.46 mM)
|
|---|---|
| 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.) |
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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
