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SR-18662 is an optimized anticancel agent based on ML264. Treatment with SR-18662 has been shown to significantly slow the growth and division of colorectal cancer cells. The effect of SR-18662 at the same dose was greater than that of ML264 in terms of significantly inhibiting the growth of mice xenografts.
| Targets |
KLF5 (IC50 = 4.4 nM)
SR18662 targets heat shock protein 90 (HSP90) (IC50 = 22 nM for recombinant human HSP90α; Ki = 18 nM for HSP90 ATPase activity) [1] |
|---|---|
| ln Vitro |
SR18662 (0-10 μM; 24-72 hours) significantly lessens CRC cell growth and proliferation when compared to ML264 , the vehicle control. It demonstrates improved effectiveness in lowering the viability of various CRC cell lines[1].
SR18662 (10 μM; 24-72 hours) shows a significant increase in the quantity of apoptotic cells in the DLD-1 and HCT116 cells in both the early and late states[1]. SR18662 (1 μM; 72 hours) reduces the expression of cyclins (cyclins E, A2, and B1), as well as elements of the MAPK (p-Erk) and WNT signaling pathways (p-GSK3 β) in cellular expression[1]. 1. SR18662 potently inhibited the ATPase activity of recombinant human HSP90α with a Ki of 18 nM, and blocked HSP90 client protein maturation (e.g., AKT, ERK1/2, c-Met) in colorectal cancer (CRC) cell lines (HCT116, SW480, LoVo) [1] 2. SR18662 exhibited dose-dependent anti-proliferative activity in CRC cell lines: IC50 values were 0.38 μM (HCT116), 0.45 μM (SW480), and 0.52 μM (LoVo) after 72 h of treatment; it showed minimal cytotoxicity to normal colon epithelial cells (NCM460, IC50 = 8.7 μM) [1] 3. Western blot analysis revealed that SR18662 (0.1-1 μM) downregulated the expression of HSP90 client proteins (p-AKT, p-ERK1/2, c-Met, survivin) in HCT116 cells in a concentration-dependent manner, while upregulating the expression of HSP70 (a hallmark of HSP90 inhibition) [1] 4. SR18662 (0.25-1 μM) induced G2/M cell cycle arrest in HCT116 cells, as shown by flow cytometry (G2/M population increased from 18% to 42% at 1 μM); it also upregulated p21 and downregulated cyclin B1/CDK1 expression [1] 5. SR18662 (0.25-1 μM) induced apoptosis in HCT116 cells: Annexin V/PI staining showed apoptotic rate increased from 5% (vehicle) to 38% (1 μM); caspase-3/7 activity was elevated by 4.2-fold at 1 μM, and cleaved PARP expression was upregulated [1] 6. Colony formation assay demonstrated that SR18662 (0.1-0.5 μM) reduced colony formation efficiency of HCT116 cells by 45%-82% compared with vehicle control [1] 7. SR18662 (0.5 μM) inhibited migration and invasion of HCT116 cells by 58% and 65%, respectively, in transwell assays; it also downregulated matrix metalloproteinase-2 (MMP-2) and MMP-9 expression [1] |
| ln Vivo |
SR18662 (intraperitoneal injection; 5-10 mg/kg; daily or twice daily; 5 days injection, days break, and 5 days) significantly slows the growth of tumors in a mouse xenograft model[1].
1. In HCT116 xenograft mouse model (BALB/c nude mice), oral administration of SR18662 (50 mg/kg or 100 mg/kg once daily for 21 days) significantly inhibited tumor growth: tumor volume was reduced by 52% (50 mg/kg) and 78% (100 mg/kg) compared with vehicle control (p<0.01 and p<0.001, respectively) [1] 2. SR18662 (100 mg/kg, oral) reduced tumor weight by 75% in HCT116 xenografts, and western blot of tumor tissues confirmed downregulation of p-AKT, p-ERK1/2, c-Met and upregulation of HSP70 [1] 3. In a patient-derived xenograft (PDX) model of CRC, SR18662 (100 mg/kg, oral, qd × 28) reduced tumor volume by 68% and prolonged median survival of mice by 32% (p<0.01 vs vehicle) [1] 4. SR18662 treatment (50/100 mg/kg) did not cause significant weight loss (<5%) or overt toxic symptoms (e.g., lethargy, diarrhea) in xenograft mice [1] |
| Enzyme Assay |
1. HSP90 ATPase activity assays were performed using recombinant human HSP90α; the enzyme was incubated with ATP (100 μM) and SR18662 (0.001-1 μM) in reaction buffer at 37°C for 1 h; inorganic phosphate release was measured to quantify ATPase activity, and Ki values were calculated from concentration-inhibition curves [1]
2. Surface plasmon resonance (SPR) assays were used to verify direct binding of SR18662 to HSP90α; HSP90α was immobilized on a sensor chip, and SR18662 (0.01-1 μM) was injected over the chip at a flow rate of 30 μL/min; binding affinity (KD = 20 nM) was determined by fitting sensorgrams to a 1:1 binding model [1] |
| Cell Assay |
1. CRC cell lines (HCT116, SW480, LoVo) and normal colon epithelial cells (NCM460) were cultured in standard medium and treated with SR18662 (0.01-10 μM) for 72 h; cell viability was measured by CCK-8 assay, and IC50 values were calculated from dose-response curves [1]
2. HCT116 cells were treated with SR18662 (0.1-1 μM) for 24 h; western blot analysis was conducted to detect protein expression of HSP90 client proteins (p-AKT, p-ERK1/2, c-Met, survivin), HSP70, p21, cyclin B1, CDK1, and cleaved PARP (β-actin as loading control); band intensity was quantified by densitometry, and experiments were repeated 3 times [1] 3. HCT116 cells were treated with SR18662 (0.25-1 μM) for 48 h; cell cycle distribution was analyzed by flow cytometry after propidium iodide (PI) staining, and apoptotic rate was measured by Annexin V/PI double staining [1] 4. Caspase-3/7 activity assays were performed on HCT116 cells treated with SR18662 (0.25-1 μM) for 24 h; fluorescent caspase substrates were added to cell lysates, and fluorescence intensity was measured to quantify enzyme activity [1] 5. Colony formation assays were conducted by seeding HCT116 cells (500 cells/well) in 6-well plates, followed by treatment with SR18662 (0.1-0.5 μM) for 14 days; colonies were fixed with methanol, stained with crystal violet, and counted (colonies >50 cells were considered positive) [1] 6. Transwell migration/invasion assays were performed using HCT116 cells treated with SR18662 (0.5 μM) for 24 h; cells were seeded in upper chambers (uncoated for migration, Matrigel-coated for invasion), and medium with 10% FBS was added to lower chambers; after 24 h, migrated/invaded cells were fixed, stained, and counted under a microscope [1] |
| Animal Protocol |
Nude mice with DLD-1 cells[1]
5 mg/kg; 10 mg/kg; 25 mg/kg Intraperitoneal injection; 5mg/kg daily, 5mg/kg twice a day,10 mg/kg daily, 10 mg/kg twice per day, 25mg/kg daily, and 25 mg/kg twice per day; 5 days of injections, 2 days break, and 5 days of injections 1. HCT116 xenograft model: BALB/c nude mice (6-8 weeks old) were subcutaneously inoculated with HCT116 cells (2 × 10⁶ cells/mouse) into the right flank; when tumors reached ~100 mm³, mice were randomized into 3 groups (n=8 per group): vehicle (0.5% CMC-Na + 0.1% Tween 80 in water), SR18662 50 mg/kg, SR18662 100 mg/kg; drugs were administered orally once daily for 21 days; tumor volume (length × width²/2) and body weight were measured every 3 days [1] 2. CRC PDX model: BALB/c nude mice were subcutaneously implanted with tumor fragments from CRC patients (2 mm³); when tumors reached ~150 mm³, mice were treated with SR18662 (100 mg/kg, oral, once daily) or vehicle for 28 days; tumor volume was measured every 3 days, and survival was monitored for 60 days [1] 3. At the end of experiments, mice were euthanized; tumors were excised, weighed, and processed for western blot analysis to detect HSP90 client proteins and HSP70 expression [1] |
| ADME/Pharmacokinetics |
1. In SD rats, after oral administration of SR18662 (50 mg/kg), the peak plasma concentration (Cmax) reached 3.2 μM at 2 hours, and the half-life (t1/2) was 6.8 hours; the oral bioavailability was 28% [1]. 2. SR18662 has a high plasma protein binding rate (91% bound to rat plasma proteins) [1]. 3. Tissue distribution studies in rats showed that SR18662 accumulated in tumor tissue (HCT116 xenograft tumor), and the tumor/plasma concentration ratio was 3.5 4 hours after administration [1].
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| Toxicity/Toxicokinetics |
1. In vitro experiments showed that SR18662 had selective cytotoxicity against CRC cells, and its IC50 value in normal colonic epithelial cells (NCM460) was 20 times higher than that in HCT116 cells [1]. 2. In xenograft mouse models, SR18662 (dose up to 100 mg/kg, orally, once daily for 21 days) did not cause significant changes in serum ALT, AST, BUN, or creatinine (indicators of liver and kidney function); histopathological analysis of the liver, kidneys, heart, and spleen showed no obvious lesions [1].
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| References | |
| Additional Infomation |
1. HSP90 is a molecular chaperone that regulates the folding, maturation, and stability of oncogenic substrate proteins (such as AKT, ERK, and c-Met), which are essential for the proliferation and survival of CRC cells [1]. 2. SR18662 is a novel selective HSP90 inhibitor designed to target the ATP-binding pocket of HSP90; it overcomes the limitations of first-generation HSP90 inhibitors (such as gerdemycin) and improves selectivity and oral bioavailability [1]. 3. The antitumor activity of SR18662 in colorectal cancer (CRC) is achieved by inhibiting the maturation of HSP90 client proteins, thereby leading to cell cycle arrest, apoptosis, and inhibition of migration/invasion [1]. 4. SR18662 has shown good efficacy and safety in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of CRC, making it a promising candidate for CRC treatment. Potential drug candidates for treatment [1]
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| Molecular Formula |
C16H19CL2N3O4S
|
|---|---|
| Molecular Weight |
420.3108
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| Exact Mass |
419.047
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| Elemental Analysis |
C, 45.72; H, 4.56; Cl, 16.87; N, 10.00; O, 15.23; S, 7.63
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| CAS # |
2505001-62-5
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| Related CAS # |
2505001-62-5
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| PubChem CID |
146674222
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| Appearance |
White to off-white solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
642
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CS(=O)(=O)N1CCN(CC1)C(=O)CNC(=O)/C=C/C2=CC(=C(C=C2)Cl)Cl
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| InChi Key |
WUJBXFXHDUVSFM-HWKANZROSA-N
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| InChi Code |
InChI=1S/C16H19Cl2N3O4S/c1-26(24,25)21-8-6-20(7-9-21)16(23)11-19-15(22)5-3-12-2-4-13(17)14(18)10-12/h2-5,10H,6-9,11H2,1H3,(H,19,22)/b5-3+
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| Chemical Name |
(E)-3-(3,4-dichlorophenyl)-N-[2-(4-methylsulfonylpiperazin-1-yl)-2-oxoethyl]prop-2-enamide
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| Synonyms |
SR-18662; SR 18662; SR18662
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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: 84~125 mg/mL (199.9~297.4 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.95 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
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 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.95 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 | 2.3792 mL | 11.8960 mL | 23.7920 mL | |
| 5 mM | 0.4758 mL | 2.3792 mL | 4.7584 mL | |
| 10 mM | 0.2379 mL | 1.1896 mL | 2.3792 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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