| Size | Price | Stock | Qty |
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| 50mg |
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| 100mg |
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| 500mg |
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| 1g | |||
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| Targets |
Opevesostat targets cytochrome P450 11A1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, which catalyzes the conversion of cholesterol to pregnenolone—the first and rate-limiting step in steroid hormone biosynthesis. It is a potent, selective, nonsteroidal, and orally bioavailable CYP11A1 inhibitor. The compound exhibits an IC50 of 15 nM for inhibition of pregnenolone biosynthesis in NCI-H295R adrenocortical carcinoma cells and demonstrates >1,000-fold selectivity over major CYP isoforms.
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| ln Vitro |
In vitro, opevesostat exhibits potent and selective inhibition of CYP11A1 with an IC50 of 15 nM in NCI-H295R adrenocortical carcinoma cells. It demonstrates rapid, complete, durable, and reversible inhibition of steroid hormone biosynthesis in adrenocortical carcinoma cell models. The compound shows >1,000-fold selectivity over major drug-metabolizing CYP isoforms, supporting its target engagement profiling and off-target evaluation. Opevesostat suppresses production of all adrenal steroid hormones and precursors through complete blockade of the steroidogenesis pathway.
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| ln Vivo |
In vivo, opevesostat has demonstrated rapid, complete, durable, and reversible inhibition of steroid hormone biosynthesis in adult noncastrated male mice and dogs. In patients with castration-resistant prostate cancer (CRPC), the compound achieves undetectable serum steroids. In the CYPIDES trial, opevesostat produced a 68% PSA response in AR LBD mutation-positive mCRPC patients. It is currently being evaluated in Phase 3 clinical trials (NCT06136624, NCT06136650) for metastatic castration-resistant prostate cancer.
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| Enzyme Assay |
The in vitro enzyme assay for opevesostat involves measuring CYP11A1 enzymatic activity in cell-free systems or in cultured cells. In NCI-H295R adrenocortical carcinoma cells, the compound is added at various concentrations, and pregnenolone biosynthesis is measured to determine the IC50 for CYP11A1 inhibition. Selectivity profiling is conducted using a panel of recombinant CYP isoforms (e.g., CYP3A4, CYP2D6, CYP2C9) to assess off-target inhibition. Enzyme activity is typically quantified by LC-MS/MS analysis of steroid metabolites produced from cholesterol or other substrates.
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| Cell Assay |
The in vitro cell-based assay for opevesostat is performed using NCI-H295R adrenocortical carcinoma cells, which express CYP11A1 and produce steroid hormones. Cells are seeded in multi-well plates and treated with opevesostat at a range of concentrations (typically 0.1-1000 nM) for a defined period (e.g., 24-48 hours). Following treatment, culture media are collected and analyzed for pregnenolone and other steroid hormone levels using immunoassay or LC-MS/MS. The IC50 value is calculated from the dose-response curve. Cell viability may be assessed using standard assays to distinguish antiproliferative effects from enzyme inhibition.
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| Animal Protocol |
In vivo animal studies for opevesostat have been conducted in adult noncastrated male mice and dogs to evaluate its pharmacodynamic effects on steroid hormone suppression. Animals are administered opevesostat orally at various doses, and blood samples are collected at multiple time points for measurement of steroid hormone levels (e.g., testosterone, cortisol, aldosterone, and their precursors). In mouse xenograft models of prostate cancer, tumor growth inhibition and PSA response are assessed following oral administration of the compound. Clinical trials in patients with mCRPC are ongoing.
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| ADME/Pharmacokinetics |
Opevesostat is an orally bioavailable small molecule with favorable pharmacokinetic properties suitable for once- or twice-daily oral dosing. In preclinical studies, it exhibits good oral absorption and systemic exposure. The compound is metabolized primarily in the liver and has a half-life compatible with clinical dosing schedules. In humans, the standard clinical dosing regimen is 5 mg BID (twice daily). Detailed PK parameters including Cmax, Tmax, AUC, and half-life have been characterized in Phase 1 and Phase 2 clinical trials.
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| Toxicity/Toxicokinetics |
The toxicity profile of opevesostat is being characterized in ongoing clinical trials. As a CYP11A1 inhibitor that suppresses all adrenal steroid hormones, the primary on-target toxicity is expected to be adrenal insufficiency, requiring corticosteroid replacement therapy. In preclinical toxicology studies, findings may include adrenal gland hypertrophy and changes in electrolyte balance due to mineralocorticoid deficiency. The compound has been evaluated in standard safety pharmacology, genotoxicity, and repeat-dose toxicity studies in rodents and dogs. No significant off-target toxicities have been reported, consistent with its high selectivity for CYP11A1.
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| References | |
| Additional Infomation |
Opevesostat is a highly bioavailable, nonsteroidal, selective cytochrome P450 side-chain lyase (CYP11A1) inhibitor with potential antitumor activity. After oral administration, Opevesostat targets and binds to CYP11A1, inhibiting its activity and thereby blocking the synthesis of all steroid hormones and their precursors. This may inhibit the proliferation of hormone-positive tumor cells. CYP11A1 is a mitochondrial enzyme that catalyzes the conversion of cholesterol to pregnenolone (Preg), the rate-limiting first step in steroid hormone biosynthesis.
Opevesostat is an investigational compound not yet approved for clinical use. It is currently in Phase 3 clinical development for metastatic castration-resistant prostate cancer (mCRPC). The compound is being evaluated in two Phase 3 trials, OMAHA1 (NCT06136624) and OMAHA2 (NCT06136650), comparing opevesostat plus corticosteroid replacement against abiraterone acetate or enzalutamide. Opevesostat represents a first-in-class approach to complete steroid ablation through CYP11A1 inhibition, addressing resistance mechanisms driven by AR ligand-binding domain mutations. |
| Molecular Formula |
C21H26N2O5S
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|---|---|
| Molecular Weight |
418.51
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| Exact Mass |
418.16
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| Elemental Analysis |
C, 60.27; H, 6.26; N, 6.69; O, 19.11; S, 7.66
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| CAS # |
2231294-96-3
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| PubChem CID |
135151902
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
763
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(CN2CC3=C(C2)C=CC=C3)OC=C(OCC2CCN(S(C)(=O)=O)CC2)C(=O)C=1
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| InChi Key |
LHVKCOBGLZGRQZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H26N2O5S/c1-29(25,26)23-8-6-16(7-9-23)14-28-21-15-27-19(10-20(21)24)13-22-11-17-4-2-3-5-18(17)12-22/h2-5,10,15-16H,6-9,11-14H2,1H3
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| Chemical Name |
2-[(1,3-dihydro-2H-isoindol-2-yl)methyl]-5-{[1-(methanesulfonyl)piperidin-4-yl]methoxy}-4H-pyran-4-one
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| Synonyms |
Opevesostat
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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 (~119.47 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.99 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 12.5 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: ≥ 1.25 mg/mL (2.99 mM) (saturation unknown) 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3894 mL | 11.9471 mL | 23.8943 mL | |
| 5 mM | 0.4779 mL | 2.3894 mL | 4.7789 mL | |
| 10 mM | 0.2389 mL | 1.1947 mL | 2.3894 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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