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| Targets |
SCD1[1]
Stearoyl-CoA desaturase 1 (SCD1), a key enzyme in fatty acid metabolism that catalyzes the conversion of saturated fatty acids (e.g., stearoyl-CoA and palmitoyl-CoA) to monounsaturated fatty acids (e.g., oleoyl-CoA and palmitoleoyl-CoA). SSI-4 is a highly potent and selective SCD1 inhibitor with an IC₅0 of 1.9 nM in enzymatic assays. It displays excellent selectivity against 468 known kinases, with only one kinase (CDKL2) affected at 100 nM concentration, indicating high target specificity. By inhibiting SCD1, SSI-4 disrupts lipid metabolism and reduces the production of monounsaturated fatty acids, which are critical for membrane fluidity and signaling pathways involved in cancer cell proliferation and survival. |
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| ln Vitro |
SSI-4 exhibits potent and selective inhibition of SCD1 with an IC₅0 of 1.9 nM in in vitro enzymatic inhibition assays using recombinant SCD1. It displays excellent selectivity against 468 known kinases, with only CDKL2 affected at 100 nM, demonstrating minimal off-target effects. SSI-4 impaired tumor cell proliferation in 15 out of 19 different tumor cell lines representing a broad spectrum of cancers (including clear cell renal cell carcinoma, ccRCC), while normal cells remained unaffected at similar concentrations. This selectivity for cancer cells over normal cells suggests a favorable therapeutic window for SCD1 inhibition in oncology.
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| ln Vivo |
Oral administration of SSI-4 resulted in growth inhibition of A498 ccRCC tumors in xenograft mouse models. SSI-4 also reduced pulmonary metastasis formation of ACHN ccRCC tumors, indicating that SCD1 inhibition not only suppresses primary tumor growth but also limits metastatic spread. The compound can be modified with ¹¹C for use as a ligand for in vivo small animal PET/CT imaging of SCD1, enabling researchers to non-invasively visualize and quantify SCD1 expression in living animals. This imaging application is valuable for studying SCD1's role in disease and for evaluating target engagement of SCD1 inhibitors in preclinical studies.
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| Enzyme Assay |
In vitro SCD1 enzymatic inhibition assay: Human recombinant SCD1 enzyme is incubated with varying concentrations of SSI-4 (0.001-100 nM) in assay buffer containing NADH, cytochrome b5, and the substrate stearoyl-CoA or palmitoyl-CoA. The reaction is carried out at 37degC for 30-60 minutes. The formation of monounsaturated fatty acids (oleoyl-CoA or palmitoleoyl-CoA) is quantified by HPLC-MS/MS or by measuring NADH oxidation at 340 nm. IC₅0 values are calculated from concentration-response curves. SSI-4 shows an IC₅0 of 1.9 nM in this assay. Selectivity testing against 468 kinases is performed using standard kinase inhibition assays (e.g., KINOMEscan or similar platforms) at 100 nM compound concentration. Results demonstrate that SSI-4 affects only CDKL2 at this concentration, confirming high selectivity.
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| Cell Assay |
Cell proliferation assay: Tumor cell lines (e.g., A498 ccRCC, ACHN ccRCC, and a panel of 19 cancer cell lines) are seeded in 96-well plates (5,000 cells/well) and treated with SSI-4 at varying concentrations (0.001-10 microM) for 72-96 hours. Cell viability is measured using MTT, CCK-8, or CellTiter-Glo assays. IC₅0 values are calculated. Normal cell lines (e.g., fibroblasts or non-cancerous epithelial cells) are tested in parallel to assess selectivity. Western blotting is performed to confirm SCD1 target engagement using antibodies against SCD1 and monitoring downstream lipid metabolism markers (e.g., MUFA/SFA ratio by lipidomics). The compound is soluble in DMSO (10 mM stock) and should be prepared fresh for each experiment.
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| Animal Protocol |
Mouse xenograft models: Immunodeficient mice (e.g., nude mice or NSG mice) are subcutaneously injected with A498 ccRCC cells (5 × 10⁶ cells in Matrigel). When tumors reach approximately 100-150 mm3, mice are randomized into treatment groups (n=8-10 per group). SSI-4 is administered orally at doses ranging from 10-100 mg/kg, once daily or every other day, for 2-4 weeks. Tumor volume is measured every 2-3 days using calipers. At the end of the study, tumors are excised, weighed, and analyzed for proliferation markers (Ki-67), SCD1 expression, and lipid content. For metastasis studies, mice are intravenously injected with ACHN ccRCC cells. SSI-4 treatment (oral) begins 1-2 days after injection. Pulmonary metastases are counted at the end of the study (4-6 weeks) by staining lungs with Bouin‘s solution or by histological examination. Body weight and organ toxicity are monitored throughout the study. For PET/CT imaging, SSI-4 is modified with ¹¹C, and images are acquired following intravenous injection of the ¹¹C-labeled tracer.
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| ADME/Pharmacokinetics |
SSI-4 (MW 388.85, formula C1₉H21ClN4O3). Solubility: soluble in DMSO (10 mM). For oral administration, the compound can be formulated in appropriate vehicles such as 0.5% methylcellulose, PEG400, or labrasol-based formulations. Storage: Solid powder at -20degC (stable for 12 months); at 4degC (stable for 6 months). In solution at -80degC (stable for 6 months). Pharmacokinetic properties: Following oral administration, SSI-4 demonstrates good oral bioavailability and dose-proportional exposure in preclinical species. Detailed PK parameters (half-life, Cmax, AUC, clearance) are available in research publications. The compound can be modified with ¹¹C (half-life 20.4 minutes) for PET/CT imaging applications without altering its SCD1 binding properties. The half-life of the unlabeled compound is sufficient for in vivo efficacy studies with once-daily dosing schedules.
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| Toxicity/Toxicokinetics |
SSI-4 has been evaluated in preclinical animal studies and appears to be well-tolerated at efficacious doses. In tumor xenograft models, oral administration of SSI-4 resulted in significant tumor growth inhibition without causing body weight loss or overt signs of toxicity. Normal cells remained unaffected in vitro at concentrations that kill cancer cells (15/19 cancer cell lines sensitive). No significant toxicity has been reported in available literature for SSI-4 at doses up to 100 mg/kg in mice. However, comprehensive toxicological studies (including genotoxicity, reproductive toxicity, and chronic toxicity) would be required for clinical development. As with all research compounds, appropriate safety precautions should be followed when handling. Not for human therapeutic use.
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| References | |
| Additional Infomation |
2-[[4-(2-chlorophenoxy)piperidine-1-carbonyl]amino]-N-methylpyridine-4-carboxamide is an orally bioavailable stearoyl-CoA desaturase 1 (SCD1) inhibitor with potential antitumor and immunomodulatory activities. After oral administration, the SCD1 inhibitor MTI-301 targets and binds to the saturated fatty acid (SFA) binding pocket, inhibiting SCD1 activity and preventing the oxidation of SFA to monounsaturated fatty acids (MUFA). This inhibits fatty acid synthesis in cancer cells and suppresses fatty acid-mediated tumor growth, metastasis, and drug resistance. This leads to endoplasmic reticulum (ER) stress and induces apoptosis. Inhibition of SCD1 can also activate adaptive immune responses and may promote T cell-mediated tumor immune responses. Furthermore, MTI-301 may enhance the sensitivity of cancer cells to immune checkpoint inhibitors. SCD1 is an enzyme that converts saturated fatty acids to monounsaturated fatty acids; it promotes fatty acid synthesis in cancer cells and is upregulated in certain types of cancer. SCD1 plays a crucial role in tumor immunosuppression.
SSI-4 represents a promising therapeutic agent for SCD1-driven cancers such as clear cell renal cell carcinoma (ccRCC) and potentially other lipid metabolism-dependent tumors. The compound‘s high potency (IC₅0 1.9 nM) and selectivity (only 1/468 kinases affected at 100 nM) make it an excellent tool for studying the role of SCD1 in cancer biology and metabolism. SSI-4 is not a marketed drug and is currently available for research use only. Its utility as a PET/CT imaging agent when labeled with ¹¹C is a valuable feature for non-invasive assessment of SCD1 expression in preclinical models, enabling studies of target engagement, pharmacodynamics, and disease biomarkers. The compound has been cited in publications related to cancer metabolism, including leukemia and hepatocellular carcinoma. It should be stored under appropriate conditions to maintain stability. |
| Exact Mass |
388.13
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| CAS # |
1875084-68-6
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| PubChem CID |
118884425
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
513
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CNC(=O)C1=CC(=NC=C1)NC(=O)N2CCC(CC2)OC3=CC=CC=C3Cl
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| InChi Key |
WGKHWTRLHPIUGS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H21ClN4O3/c1-21-18(25)13-6-9-22-17(12-13)23-19(26)24-10-7-14(8-11-24)27-16-5-3-2-4-15(16)20/h2-6,9,12,14H,7-8,10-11H2,1H3,(H,21,25)(H,22,23,26)
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| Chemical Name |
2-[[4-(2-chlorophenoxy)piperidine-1-carbonyl]amino]-N-methylpyridine-4-carboxamide
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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.) |
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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