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Purity: ≥98%
CBR-5884 is a novel, potent, and selective inhibitor of phosphoglycerate dehydrogenase (PHGDH) with an IC50 of 33 μM and with anticancer activities. CBR-5884 inhibits de novo serine synthesis in cancer cells and is selectively toxic to cancer cell lines with high serine biosynthetic activity. CBR-5884 selectively inhibits the proliferation of melanoma and breast cancer lines that have a high propensity for serine synthesis. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH.
| Targets |
Phosphoglycerate dehydrogenase/PHGDH
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|---|---|
| ln Vitro |
CBR-5884 (15 or 30 μM; 3-5 days) specifically prevents breast cancer and melanoma cell lines that have a strong propensity for serine synthesis from proliferating.
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| ln Vivo |
In vivo studies revealed that CBR-5884 significantly delayed tumor growth, with histological analysis indicating the safety profile of CBR-5884. Finally, the patient-derived organoid (PDO) models were utilized to explore the preclinical efficacy of CBR-5884 against EOC cells, and the results unveiled that CBR-5884 impeded proliferation and downregulated the expression of ITGB4 in EOC PDO models. [2]
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| Enzyme Assay |
Screening for Small Molecule Inhibitors of PHGDH. [1]
An in vitro enzymatic assay for PHGDH activity amenable to high-throughput screening (HTS) was developed by coupling the production of NADH, upon 3-PG oxidation, to the reduction of resazurin to resorufin using diaphorase as the coupling enzyme. Thus, resorufin fluorescence served as a proxy for PHGDH activity. The assay was miniaturized to a 1,536-well format with a Z-factor of >0.75, indicating a high quality assay. A library of 800,000 small molecules was screened in single point format at 13 μM. Setting a threshold Z score of −3, corresponding to at least 50% PHGDH inhibition, gave a 0.5% hit rate, yielding 3,906 hits. Putative hits were reassayed in triplicate and counter-screened against diaphorase to rule out false positives targeting diaphorase. The counter screen eliminated 3,498 compounds, giving 408 PHGDH inhibitors. A triaging strategy based on hit potency and selectivity was designed. We reasoned that inhibitors specific to PHGDH would minimize general cellular toxicity compared with compounds that hit a variety of dehydrogenases. Thus, half maximal inhibitory concentrations (IC50) were determined for a panel of NAD(P)+-dependent dehydrogenases that included PHGDH, isocitrate dehydrogenase (IDH1), malate dehydrogenase (MDH1), and 3α-hydroxysteroid dehydrogenase (3α-HSD). Compounds at least fourfold more selective for PHGDH were progressed for further analysis. Based on this triaging, seven of the most potent PHGDH inhibitors were selected as lead compounds for evaluation in cell-based assays; selected structures are shown in Fig. 1E. A number of these compounds are likely to target sulfhydryl groups and may therefore react with a PHGDH cysteine residue. For example, both CBR-5807 and CBR-6936 contain sulfhydryl-reactive disulfide centers. Interestingly, CBR-5807 (Disulfiram) is an approved drug dosed in humans to treat alcoholism and known to inhibit aldehyde dehydrogenase by reacting with sulfhydryl groups.[1] |
| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Breast cancer and melanoma cell lines Tested Concentrations: 15 or 30 μM Incubation Duration: 3-5 days Experimental Results: Inhibited proliferation of melanoma and breast cancer cell lines. |
| Animal Protocol |
The study utilized 12 female BALB/c nude mice aged 4–6 weeks, procured from the Experimental Animal Center of Southern Medical University. These mice were housed in autoclaved, ventilated cages and provided with autoclaved water. All mice used were bred in the specific pathogen free laboratory. The mice received a subcutaneous injection of 1 × 106 ID8 cells in the right armpit. When the tumors reached an average volume of 65 mm3, the mice were randomly divided into two groups using the random number method: (1) an experimental group, wherein the mice received intragastric administration of CBR-5884 (70 mg/kg, qd; n = 6); and (2) a control group, wherein the mice received intragastric administration of an equal volume of vehicle (corn oil) (n = 6). CBR-5884 treatment lasted for 12 consecutive days, with continuous drug administration. Tumors were resected when the average tumor volume in the control group reached 400 mm3. Tumor growth was tracked using caliper measurements, and tumor volume was calculated using the formula: length × width2/2. Subsequently, images of mice and tumors were captured, and tumors were weighed. Liver, spleen, kidney, and tumors were subjected to histological analysis after hematoxylin–eosin (H&E) staining. The maximal tumor size/burden permitted by our institutional review board is 10% of body weight and mean tumor diameter = or > 15 mm in adult mice (~ 25 g). The maximal tumor size/burden permitted by our institutional review board was not exceeded.[2]
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| References | |
| Additional Infomation |
Reprogramming of the serine synthesis pathway (SSP) is intricately linked to the progression of epithelial ovarian cancer (EOC). CBR-5884, a selective small-molecule inhibitor targeting phosphoglycerate dehydrogenase (PHGDH), effectively impedes the de novo synthesis of serine within cancer cells. This study aimed to evaluate the inhibitory effect of CBR-5884 on EOC cells and delineate its specific mechanism, thereby proposing a novel therapeutic approach for treating EOC. The suppression of serine biosynthesis after CBR-5884 treatment was evaluated using RNA sequencing and a serine assay kit, and the results showed that CBR-5884 effectively downregulated serine biosynthesis in EOC cells, particularly those expressing high levels of PHGDH. In vitro studies revealed that CBR-5884 demonstrated significant antitumor effects and suppressed migration and invasion of EOC cells through down-regulation of the integrin subunit beta 4 (ITGB4)/extracellular signal-regulated kinase (ERK)/epithelial–mesenchymal transition signal axis. Additionally, CBR-5884 mitigated the stemness of EOC cells and heightened their sensitivity to chemotherapy. Moreover, in vivo studies revealed that CBR-5884 significantly delayed tumor growth, with histological analysis indicating the safety profile of CBR-5884. Finally, the patient-derived organoid (PDO) models were utilized to explore the preclinical efficacy of CBR-5884 against EOC cells, and the results unveiled that CBR-5884 impeded proliferation and downregulated the expression of ITGB4 in EOC PDO models. Our findings supports the anticancer properties of CBR-5884 in EOC cells exhibiting high PHGDH expression, manifesting through the suppression of proliferation, migration, and invasion, while enhancing chemotherapy sensitivity, suggesting that CBR-5884 holds promise as an efficacious strategy for the treatment of EOC[2].
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| Molecular Formula |
C14H12N2O4S2
|
|---|---|
| Molecular Weight |
336.386
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| Exact Mass |
336.023
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| Elemental Analysis |
C, 49.99; H, 3.60; N, 8.33; O, 19.02; S, 19.06
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| CAS # |
681159-27-3
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| PubChem CID |
4674993
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| Appearance |
Typically exists as light yellow to yellow solids at room temperature
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
378.1±42.0 °C at 760 mmHg
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| Flash Point |
182.5±27.9 °C
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| Vapour Pressure |
0.0±0.9 mmHg at 25°C
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| Index of Refraction |
1.628
|
| LogP |
4.15
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
22
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| Complexity |
479
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=C(C)C(SC#N)=C(NC(C2=CC=CO2)=O)S1)OCC
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| InChi Key |
QBVIRPJBDIZKBC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H12N2O4S2/c1-3-19-14(18)11-8(2)10(21-7-15)13(22-11)16-12(17)9-5-4-6-20-9/h4-6H,3H2,1-2H3,(H,16,17)
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| Chemical Name |
ethyl 5-(furan-2-carboxamido)-3-methyl-4-thiocyanatothiophene-2-carboxylate
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| Synonyms |
CBR-5884; CBR 5884; CBR5884.
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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 |
| 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 : ~50 mg/mL (~148.64 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.18 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9727 mL | 14.8637 mL | 29.7274 mL | |
| 5 mM | 0.5945 mL | 2.9727 mL | 5.9455 mL | |
| 10 mM | 0.2973 mL | 1.4864 mL | 2.9727 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.
 Activity of PHGDH CBR-5884 in cells.Proc Natl Acad Sci U S A.2016 Feb 16;113(7):1778-83. |
|---|
 CBR-5884 inhibits serine synthesis in cells.Proc Natl Acad Sci U S A.2016 Feb 16;113(7):1778-83. |
 CBR-5884 selectively inhibits the proliferation of breast cancer lines with a high propensity for serine synthesis.Proc Natl Acad Sci U S A.2016 Feb 16;113(7):1778-83. |
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