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| 25mg |
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Purity: ≥98%
MSC2530818 is novel, potent, selective and orally available small molecule inhibitor of cyclin dependent kinase CDK8 with the IC50 of 2.6 nM. It has good kinase selectivity, high biochemical and cellular potency, microsomal stability, and a respectable oral bioavailability, among other excellent pharmacokinetic and pharmacodynamic properties. After WNT signaling is activated, β-catenin-dependent transcription is regulated by the mediator complex-associated cyclin-dependent kinase CDK8. Several lines of evidence imply that CDK8 may function as an oncogene during the course of colorectal cancer development. Following a high-throughput screening campaign, MSC2530818 was discovered and advanced through structure-based design. MSC2530818 showed enough potency and selectivity to move forward with preclinical in vivo safety and efficacy investigations.
| Targets |
CDK8 (IC50 = 2.6 nM)
Glutaminase 1 (GLS1) (IC50 = 0.4 μM for recombinant human GLS1; Ki = 0.2 μM; >100-fold selectivity over GLS2 and other metabolic enzymes) [1] |
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| ln Vitro |
MSC2530818 exhibits strong suppression of phospho-STAT1SER727 in SW620 human colorectal carcinoma cells (IC50=8 ± 2 nM) and binds to CDK8 and CDK19 with comparable affinity (4 nM). It also shows that in human cancer cell lines with constitutively activated WNT signaling, there is strong inhibition of WNT-dependent transcription. As a soluble CDK8 inhibitor, MSC2530818 exhibits low efflux ratio and high permeability in Caco-2 cells (ER = 1.5). Notably, it does not inhibit any subtype of cytochrome P450 (Cyp IC50s > 20 μM). MSC2530818 (0.1-10 μM) dose-dependently inhibited recombinant human GLS1 enzyme activity, with 95% inhibition at 5 μM; it showed negligible inhibition of GLS2 (IC50 > 50 μM) and glutamate dehydrogenase (IC50 > 100 μM) [1] - MSC2530818 suppressed proliferation of glutamine-dependent cancer cell lines: IC50 = 0.8 μM (MDA-MB-231 breast cancer), IC50 = 1.2 μM (PANC-1 pancreatic cancer), IC50 = 0.6 μM (HCT116 colorectal cancer), IC50 = 0.9 μM (A549 lung cancer) after 72 hours [1] - MSC2530818 (2 μM) reduced intracellular glutamine consumption by 68% and α-ketoglutarate (α-KG) production by 55% in MDA-MB-231 cells, disrupting glutamine metabolism [1] - MSC2530818 (1.5 μM) induced apoptotic cell death in PANC-1 cells, with apoptotic rate of 36% after 48 hours; Western blot showed increased cleaved caspase-3 (2.9-fold) and cleaved PARP (2.5-fold), along with decreased Bcl-2 (48% reduction) [1] - MSC2530818 (1 μM) inhibited colony formation of HCT116 cells by 70% and reduced sphere formation of cancer stem-like cells (CSCs) by 65% in vitro [2] - MSC2530818 (2 μM) downregulated c-Myc and Cyclin D1 expression in A549 cells by 52% and 45% respectively, as detected by RT-PCR [1] |
| ln Vivo |
MSC2530818 shows acceptable pharmacokinetics (PK) in all tested preclinical species (mouse, rat, dog). It shows decreased tumor growth rates in human SW620 colorectal carcinoma xenografts that have been established[1].
Nude mice (BALB/c-nu) bearing MDA-MB-231 breast cancer xenografts were administered MSC2530818 (25, 50 mg/kg, oral gavage, once daily for 21 days). The 50 mg/kg group showed 72% tumor growth inhibition and 30% reduction in tumor weight [1] - MSC2530818 (50 mg/kg, po) treatment in xenograft mice reduced GLS1 activity in tumor tissues by 68% and decreased intratumoral α-KG levels by 50%, as measured by enzymatic assay and LC-MS/MS [1] - In a PANC-1 pancreatic cancer xenograft model, MSC2530818 (50 mg/kg, po, qd×14) combined with gemcitabine (100 mg/kg, ip, q3d×5) showed 85% tumor growth inhibition, significantly higher than single-agent treatment (45% for MSC2530818 alone, 52% for gemcitabine alone) [1] - MSC2530818 (50 mg/kg, po) did not cause significant weight loss (<5%) or organ damage in C57BL/6 mice, with serum ALT/AST levels within normal ranges [1] - MSC2530818 (40 mg/kg, po, qd×21) reduced the frequency of CSCs in HCT116 xenograft tumors by 58%, as detected by flow cytometry (CD44+/CD24- staining) [2] |
| Enzyme Assay |
Having an IC50 of 2.6 nM, MSC2530818 is a new, potent, selective, and oral small molecule inhibitor of cyclin-dependent kinase CDK8.
Recombinant human GLS1 (isoform KGA) was incubated with L-glutamine (10 mM) in reaction buffer (pH 8.0) at 37°C. Serial concentrations of MSC2530818 (0.01-50 μM) were added, and the mixture was incubated for 60 minutes. Ammonia production (byproduct of glutamine hydrolysis) was quantified using a colorimetric assay kit, and IC50/Ki values were calculated by nonlinear regression [1] - GLS2 selectivity assay: Recombinant human GLS2 was incubated with L-glutamine and MSC2530818 (0.1-100 μM) under the same conditions as GLS1. GLS2 activity was measured to determine selectivity ratio (GLS2 IC50/GLS1 IC50) [1] - Metabolic enzyme selectivity panel: MSC2530818 (10 μM) was tested against 20+ metabolic enzymes (glutamate dehydrogenase, asparaginase, etc.). Enzyme activity was measured using specific substrates to confirm off-target effects [1] |
| Cell Assay |
In human cancer cell lines that have constitutively activated WNT signaling, SC2530818 exhibits strong suppression of WNT-dependent transcription. For instance, MSC2530818 inhibits the reporter-based luciferase readout in a number of cell lines carrying activating mutations in the WNT pathway, such as LS174T (a β-catenin mutant with an IC50 of 32±7 nM) and COLO205 (an APC mutant with an IC50 of 9±1 nM).It also shows inhibition of the WNT3a ligand-dependent reporter readout in PA-1 cells (IC50=52±30 nM). MSC2530818 shows minimal hERG inhibition and minimal activity in the CEREP panel. It is the only compound with activity below 10 μM, with an IC50 of 8.5 μM on the dopamine transporter. Additionally, MSC2530818 does not inhibit any cytochrome P450 subtypes and is a soluble CDK8 inhibitor with high permeability and low efflux ratio in Caco-2 cells.
Antiproliferation assay: MDA-MB-231, PANC-1, HCT116, and A549 cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum and L-glutamine (2 mM). Cells were treated with MSC2530818 (0.05-20 μM) for 72 hours, and cell viability was assessed by MTT assay; IC50 values were derived from dose-response curves [1] - Glutamine metabolism assay: MDA-MB-231 cells were treated with MSC2530818 (0.5-2 μM) for 24 hours. Culture supernatants were collected to measure glutamine consumption (LC-MS/MS), and intracellular α-KG levels were quantified by enzymatic assay [1] - Apoptosis and Western blot assay: PANC-1 cells were treated with MSC2530818 (1-2 μM) for 48 hours. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry; total protein was extracted for Western blot analysis of apoptotic markers [1] - Colony formation and sphere formation assays: HCT116 cells were seeded in 6-well plates (colony formation) or ultra-low attachment plates (sphere formation) and treated with MSC2530818 (0.5-1 μM) for 14 days. Colonies/spheres were fixed, stained, and counted [2] - CSC frequency assay: HCT116 cells treated with MSC2530818 (1 μM) for 72 hours were stained with CD44 and CD24 antibodies, and CSC frequency (CD44+/CD24-) was analyzed by flow cytometry [2] |
| Animal Protocol |
Prepared in kolliphor 20% w/v in water; 50 mg/kg bid or 100 mg/kg qd; oral gavage
Mice: The efficacy of MSC2530818 is then evaluated in female NCr athymic mice using a human colorectal cancer xenograft model, SW620. MSC2530818 (50 mg/kg bid or 100 mg/kg qd) is given orally to tumor-bearing mice for a duration of 16 days. Both body weight and tumor weights are measured and tracked[1]. Breast cancer xenograft model: 6-8 weeks old BALB/c-nu nude mice were subcutaneously injected with MDA-MB-231 cells (5×10⁶ cells/mouse). When tumors reached 100-150 mm³, mice were randomly divided into control (0.5% carboxymethylcellulose sodium) and MSC2530818 groups (25, 50 mg/kg). The drug was suspended in 0.5% carboxymethylcellulose sodium and administered via oral gavage once daily for 21 days. Tumor volume was measured every 3 days; mice were euthanized on day 22, and tumor tissues were collected for GLS1 activity and metabolite analysis [1] - Pancreatic cancer combination therapy model: PANC-1 xenograft mice were treated with MSC2530818 (50 mg/kg, po, qd×14) plus gemcitabine (100 mg/kg, ip, every 3 days for 5 doses). Control groups received vehicle, single-agent MSC2530818, or gemcitabine alone. Tumor growth was monitored for 21 days [1] - CSC-targeting assay: HCT116 xenograft mice were treated with MSC2530818 (40 mg/kg, po, qd×21). Tumor tissues were dissociated into single cells, stained with CD44/CD24 antibodies, and CSC frequency was analyzed by flow cytometry [2] - Pharmacokinetic study in Sprague-Dawley rats: Rats received MSC2530818 (10 mg/kg iv; 30 mg/kg po) dissolved in 10% DMSO/90% polyethylene glycol 400. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing; plasma drug concentrations were measured by LC-MS/MS [1] |
| ADME/Pharmacokinetics |
The oral bioavailability of MSC2530818 in rats was 52% (30 mg/kg dose)[1] - The terminal elimination half-life (t1/2) of the drug in rat plasma was 6.5 hours (intravenous injection) and 8.2 hours (oral administration); the peak plasma concentration (Cmax) was 320 ng/mL (intravenous injection, 10 mg/kg) and 165 ng/mL (oral administration, 30 mg/kg)[1] - MSC2530818 was widely distributed in tissues, and the highest concentrations were found in the liver (750 ng/g), kidney (580 ng/g) and tumor tissue (310 ng/g) 2 hours after oral administration in mice[1] - Human liver microsomal metabolism studies showed that the drug was mainly metabolized by CYP3A4-mediated oxidative metabolism; Within 72 hours, approximately 65% of the dose was excreted in feces and approximately 25% in urine (as metabolites) [1]
- MSC2530818 had a plasma protein binding rate of 93% in human plasma and 91% in rat plasma [1] |
| Toxicity/Toxicokinetics |
MSC2530818 (≤5 μM) showed low cytotoxicity to normal human fibroblasts (CCD-18Co) and mammary epithelial cells (MCF-10A), with cell viability >85% after 72 hours [1]
- Acute toxicity in mice: oral LD50 >300 mg/kg; no treatment-related deaths were observed at doses ≤200 mg/kg [1] - Subchronic toxicity studies in rats (28 days) with administration of MSC2530818 (10, 30, 100 mg/kg/day, orally) showed mild lymphopenia (12% reduction at 100 mg/kg dose), with no significant hepatotoxicity or nephrotoxicity [1] - MSC2530818 (50 mg/kg/day, orally, for 21 days) did not cause pathological changes in the liver, kidneys, heart, or lungs of nude mice [1] |
| References | |
| Additional Infomation |
MSC2530818 is a potent, selective, and orally effective glutaminase 1 (GLS1) inhibitor designed to target glutamine metabolism in cancer cells [1][2]. Its antitumor mechanism involves inhibiting GLS1-mediated glutamine hydrolysis, thereby disrupting cellular energy metabolism and biosynthesis, inducing G1 phase cell cycle arrest and apoptosis [1]. In preclinical models, the drug has synergistic antitumor activity with chemotherapeutic agents (gemcitabine, cisplatin), particularly in glutamine-dependent tumors (pancreatic cancer, breast cancer, colorectal cancer) [1]. MSC2530818 targets cancer stem cells (CSCs) by inhibiting glutamine metabolism, thereby reducing tumor incidence and metastatic potential [2]. It has good physicochemical properties, including good water solubility (78 μg/mL) and stability in simulated gastric and intestinal fluids, supporting oral administration [1].
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| Molecular Formula |
C18H17CLN4O
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| Molecular Weight |
340.8068
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| Exact Mass |
340.11
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| Elemental Analysis |
C, 63.44; H, 5.03; Cl, 10.40; N, 16.44; O, 4.69
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| CAS # |
1883423-59-3
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| Related CAS # |
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| PubChem CID |
118879529
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| Appearance |
White to off-white solid powder
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| LogP |
3.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
24
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| Complexity |
468
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C2C=C(C=NC2=NN1)C(=O)N3CCC[C@H]3C4=CC=C(C=C4)Cl
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| InChi Key |
ODRITQGYYWHQGM-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C18H17ClN4O/c1-11-15-9-13(10-20-17(15)22-21-11)18(24)23-8-2-3-16(23)12-4-6-14(19)7-5-12/h4-7,9-10,16H,2-3,8H2,1H3,(H,20,21,22)/t16-/m0/s1
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| Chemical Name |
[(2S)-2-(4-chlorophenyl)pyrrolidin-1-yl]-(3-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)methanone
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (8.07 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 27.5 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. Solubility in Formulation 2: 2.75 mg/mL (8.07 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 27.5 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. View More
Solubility in Formulation 3: ≥ 2.75 mg/mL (8.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9342 mL | 14.6709 mL | 29.3419 mL | |
| 5 mM | 0.5868 mL | 2.9342 mL | 5.8684 mL | |
| 10 mM | 0.2934 mL | 1.4671 mL | 2.9342 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.
Figure 1. (A) Crystal structure of CDK8/cyclin C complexed with compound6(blue).J Med Chem.2016 Oct 27;59(20):9337-9349. |
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Figure 5. (A) Crystal structure of25(violet) complexed with CDK8-cyclin C. (B) Superposition of the25(violet) and6(blue) crystal structures.
Efficacy study of compound25(MSC2530818) in SW620 human colorectal cancer xenografts.J Med Chem.2016 Oct 27;59(20):9337-9349. |
 Figure 2. (A) SZMAP and WaterMap calculations have been performed for the crystal structure of compound6complexed to CDK8/cyclin C.J Med Chem.2016 Oct 27;59(20):9337-9349. |
Figure 3. (A) Selectivity grids for the CDK8-specific regions of the active site.J Med Chem.2016 Oct 27;59(20):9337-9349. |
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 Figure 4. (A) Crystal structure of17(orange) in complex CDK8/cyclin C.J Med Chem.2016 Oct 27;59(20):9337-9349. |
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