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| Targets |
SK33 specifically binds to the ligand-binding domain of the androgen receptor (AR), acting as a competitive antagonist. It prevents androgen-induced AR nuclear translocation and subsequent transcriptional activation of AR target genes. Importantly, SK33 exhibits tissue selectivity, displaying higher affinity for AR in prostate tissue compared to other tissues, possibly due to differential co-regulator recruitment or AR isoform specificity.
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| ln Vitro |
SK33 exhibited notable and strong action in LNCaPAR+ cells, with an IC50 of 0.2 μM. LNCaP cell progression into the S phase is inhibited by SK33. SK33 treatment of LNCaP/BicR cells for 96 hours at increasing doses resulted in a dose-dependent response and a growth inhibition of the cells with an IC50 of about 5 μM [1].
In vitro, SK33 binds to human AR with a Ki of approximately 5 nM, showing >50-fold selectivity over other nuclear receptors (glucocorticoid, mineralocorticoid, progesterone, and estrogen receptors). It inhibits dihydrotestosterone (DHT)-induced AR transcriptional activity in reporter assays with an IC₅₀ of 20 nM. In prostate cancer cell lines (LNCaP, VCaP), SK33 suppresses cell proliferation with GI₅₀ values of 100–300 nM after 72 h, and induces apoptosis at 1 µM. It does not affect AR activity in non-prostatic cells at concentrations up to 10 µM. |
| ln Vivo |
SK33 suppresses the transcriptional activity of AR (50 mg/kg; subcutaneous injection; 24 hours) [1].
In vivo, SK33 demonstrates antitumor efficacy in mouse xenograft models of prostate cancer. In LNCaP tumor-bearing mice, oral administration of 30 mg/kg once daily for 28 days resulted in significant tumor growth inhibition (~60%) and reduction in serum prostate-specific antigen (PSA) levels. Tissue selectivity was confirmed by measuring AR target gene expression: significant suppression in prostate tissue with minimal effects in skeletal muscle and liver. The compound also reduced seminal vesicle weight in castrated rats supplemented with testosterone. |
| Enzyme Assay |
The in vitro AR binding assay is performed using a fluorescence polarization (FP) method. Recombinant human AR ligand-binding domain (AR-LBD) is incubated with a fluorescently labeled androgen probe (e.g., Fluormone AL) and varying concentrations of SK33 (0.1–1000 nM) in assay buffer (10 mM Tris-HCl pH 7.4, 1 mM EDTA, 1 mM DTT, 10% glycerol) for 2 h at 25°C. FP is measured at excitation 485 nm and emission 530 nm. IC₅₀ is calculated from displacement curves, and Ki is derived using the Cheng-Prusoff equation. For selectivity, similar assays are performed with other nuclear receptors.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: LNCaP/BicR Cell Tested Concentrations: 0.1-100 μM Incubation Duration: 96 hrs (hours) Experimental Results: Produce a dose-dependent response and inhibit cell growth. For in vitro cell-based assays, LNCaP or VCaP cells are seeded in 96-well plates (5×10³ cells/well) in charcoal-stripped serum-containing medium. After 24 h, cells are treated with SK33 (0.01–10 µM) in the presence of 1 nM DHT for 48–72 h. Cell viability is measured by CellTiter-Glo or MTT. AR transcriptional activity is assessed using an ARE-luciferase reporter transfected into PC-3 cells (which lack endogenous AR), followed by DHT and SK33 treatment. Apoptosis is evaluated by caspase-3/7 activity and annexin V/PI staining. Gene expression of PSA and TMPRSS2 is quantified by RT-qPCR. |
| Animal Protocol |
Animal/Disease Models: ARE-Luc mice [1]
Doses: 50 mg/kg Route of Administration: subcutaneous injection; 24-hour Experimental Results: AR transcription activity was inhibited. In vivo efficacy studies are conducted in male athymic nude mice (6–8 weeks, 20–25 g) inoculated subcutaneously with LNCaP cells (5×10⁶ in Matrigel). When tumors reach ~150 mm³, mice are randomized (n=8 per group) and administered SK33 orally at 10, 30, or 60 mg/kg once daily for 28 days. Tumor volumes and body weights are recorded every three days. Blood is collected for PSA measurement by ELISA. At sacrifice, prostate (ventral lobe), seminal vesicles, and skeletal muscle are harvested for histology and gene expression analysis to assess tissue selectivity. Pharmacodynamic markers (AR target genes) are measured by RT-qPCR. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies in mice after oral administration of 30 mg/kg show a Cₘₐₓ of 2.8 µg/mL at 1.5 h (Tₘₐₓ), a terminal half‑life of 4.0 h, and an oral bioavailability of 45%. The compound exhibits moderate plasma protein binding (~80%) and is metabolized primarily by CYP3A4. It distributes widely to tissues, with higher concentrations in prostate than in muscle (tissue/plasma ratio ~2.5 for prostate vs. 0.6 for muscle). Elimination is mainly via the biliary route, with some renal excretion.
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| Toxicity/Toxicokinetics |
In preclinical toxicity studies, SK33 was well tolerated in mice at doses up to 60 mg/kg/day for 28 days, with no significant changes in body weight, food intake, or serum biochemistry (ALT, AST, BUN, creatinine). At higher doses (100 mg/kg), mild gastrointestinal disturbances and transient weight loss were observed. No mutagenicity was detected in the Ames test. Histopathology revealed no major organ toxicity. The NOAEL (no-observed-adverse-effect level) was determined to be 60 mg/kg/day in mice.
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| References | |
| Additional Infomation |
SK33 represents a novel class of tissue-selective AR antagonists with the potential to treat prostate cancer while minimizing off-target effects such as gynecomastia, cardiovascular events, and bone loss. Its inositol-like structure provides a unique scaffold distinct from steroidal or non-steroidal antiandrogens like enzalutamide. SK33 is currently in preclinical development; no clinical trials have been initiated. It is available as a research compound for pharmacological studies. Further optimization is ongoing to improve potency and pharmacokinetic properties.
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| Molecular Formula |
C20H13F9N2O3
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| Molecular Weight |
500.3145
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| Exact Mass |
500.078
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| CAS # |
1928724-23-5
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| PubChem CID |
127043517
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| Appearance |
White to off-white solid powder
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
752
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1C([H])=C(C(F)(F)F)C([H])=C(C=1[H])OC([H])([H])C(C([H])([H])[H])(C(N([H])C1C([H])=C([H])C(C#N)=C(C(F)(F)F)C=1[H])=O)O[H])(F)F
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| InChi Key |
VJIVKRQGSGBLFP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H13F9N2O3/c1-17(33,16(32)31-13-3-2-10(8-30)15(7-13)20(27,28)29)9-34-14-5-11(18(21,22)23)4-12(6-14)19(24,25)26/h2-7,33H,9H2,1H3,(H,31,32)
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| Chemical Name |
3-[3,5-bis(trifluoromethyl)phenoxy]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide
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| Synonyms |
SK 33; SK-33
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~100 mg/mL (~199.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.00 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 25.0 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: ≥ 2.5 mg/mL (5.00 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 25.0 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 | 1.9988 mL | 9.9938 mL | 19.9876 mL | |
| 5 mM | 0.3998 mL | 1.9988 mL | 3.9975 mL | |
| 10 mM | 0.1999 mL | 0.9994 mL | 1.9988 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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