| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Targets |
TRC253 (also named JNJ-63576253) acts as an antagonist of androgen receptor (AR), including wild-type AR (wtAR) and F877L mutant AR (AR-F877L); the Ki value for wtAR is 1.1 nM, for AR-F877L is 1.8 nM; the EC50 for wtAR transactivation inhibition is 6.2 nM, for AR-F877L transactivation inhibition is 9.4 nM [1]
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| ln Vitro |
VCaP cell proliferation is inhibited by JNJ-63576253 (0.0003-100 μM; 5 d) with an IC50 of 265 nM[1]. In human liver microsomes with T1/2 >180 minutes, JNJ-63576253 exhibits stability [1].
1. In the AR binding assay, TRC253 exhibited high affinity to wtAR (Ki = 1.1 nM) and AR-F877L (Ki = 1.8 nM), which was superior to the positive control enzalutamide (Ki for wtAR = 3.4 nM, Ki for AR-F877L > 1000 nM) [1] 2. In the AR transactivation reporter assay, TRC253 potently inhibited dihydrotestosterone (DHT)-induced wtAR transactivation with an EC50 of 6.2 nM and AR-F877L transactivation with an EC50 of 9.4 nM, while enzalutamide showed EC50 > 1000 nM for AR-F877L transactivation [1] 3. In prostate cancer cell lines, TRC253 inhibited the proliferation of LNCaP (wtAR) cells with an IC50 of 23 nM and 22Rv1 (AR-F877L) cells with an IC50 of 37 nM, whereas enzalutamide had an IC50 of >1000 nM for 22Rv1 cells [1] 4. Western blot analysis showed that TRC253 downregulated the expression of AR target genes (PSA, TMPRSS2) in both LNCaP and 22Rv1 cells in a dose-dependent manner, and inhibited AR nuclear translocation in these cells [1] |
| ln Vivo |
JNJ-63576253 (30 mg/kg; once daily, face) greatly monitors the growth of tumors expressing LNCaP SRα F877L [1]. Targeting five androgen-sensitive organs (ASOs) activated by testosterone propionate (TP), JNJ-63576253 (30 mg/kg; po once daily for 10 days) [1]. JNJ-63576253 (10 mg/kg; po) exhibits simulated bioavailability (45%), Cmax ( JNJ-63576253 (2 mg/kg; i.v.) exhibits reasonable half-life (5.99 hours), CL (15.0 mL/min/kg) 0.66 μM) and AUClast (4.9 μg h/mL).
1. In the LNCaP xenograft model (wtAR) in nude mice, oral administration of TRC253 at doses of 10 mg/kg and 30 mg/kg once daily for 28 days resulted in tumor growth inhibition (TGI) of 68% and 89%, respectively; no significant body weight loss was observed in the treated mice [1] 2. In the 22Rv1 xenograft model (AR-F877L) in nude mice, oral administration of TRC253 at 30 mg/kg once daily for 28 days achieved a TGI of 76%, while enzalutamide at 30 mg/kg showed no significant tumor inhibition in this model [1] 3. Pharmacodynamic analysis in tumor tissues from xenograft models revealed that TRC253 significantly reduced the expression of AR target genes (PSA, TMPRSS2) and inhibited AR nuclear localization, consistent with its in vitro mechanism [1] |
| Enzyme Assay |
1. For the AR binding assay, the recombinant human AR ligand-binding domain (LBD) was incubated with different concentrations of TRC253 and a radiolabeled androgen ligand; after incubation, the bound and free ligand were separated by filtration, and the radioactivity of the bound fraction was measured to calculate the Ki value of TRC253 for wtAR and AR-F877L [1]
2. For the AR transactivation enzyme-linked immunosorbent assay (ELISA), reporter gene plasmids containing AR response elements (ARE) were transfected into HEK293 cells together with wtAR or AR-F877L expression plasmids; the cells were then treated with DHT and serial concentrations of TRC253, and after incubation, the reporter gene activity was detected by ELISA to determine the EC50 of TRC253 for AR transactivation inhibition [1] |
| Cell Assay |
1. For the prostate cancer cell proliferation assay, LNCaP (wtAR) and 22Rv1 (AR-F877L) cells were seeded in 96-well plates and treated with serial concentrations of TRC253 for 72 hours; cell viability was assessed using a colorimetric cell proliferation reagent, and the IC50 values for cell proliferation inhibition were calculated from the dose-response curves [1]
2. For the AR target gene expression analysis, LNCaP and 22Rv1 cells were treated with TRC253 at different concentrations for 24 hours; total RNA was extracted from the cells, and the mRNA levels of PSA and TMPRSS2 were detected by quantitative real-time PCR (qPCR); additionally, total protein and nuclear protein were extracted, and the expression and subcellular localization of AR were analyzed by western blot [1] |
| Animal Protocol |
Animal/Disease Models: Castrated SHO mice with prostate LNCaP SRα F877L tumors [1]
Doses: 30 mg/kg Route of Administration: Po, one time/day for 72 days Experimental Results: Inhibited tumor growth by 87%. Animal/Disease Models: CD-1 male mice [1] Doses: 2 mg/kg, intravenous (iv) (iv)injection; 10 mg/kg po (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)and oral administration Experimental Results: Iv: T1 /2=5.99 h; CL=15.0 ml/min/kg; Vdss=6.11 liters/kg. Po: F=45%; Cmax=0.66μM; AUClast=4.9 μg·h/mL. 1. For the LNCaP xenograft model, male nude mice were subcutaneously inoculated with LNCaP cells into the flank; when tumors reached a volume of approximately 100 mm³, the mice were randomly divided into vehicle and treatment groups, and TRC253 was administered orally at doses of 10 mg/kg and 30 mg/kg once daily for 28 days; the drug was dissolved in a vehicle consisting of hydroxypropyl methylcellulose (HPMC) and Tween 80 in water, and tumor volume and body weight were measured twice weekly [1] 2. For the 22Rv1 xenograft model, male nude mice were subcutaneously inoculated with 22Rv1 cells into the flank; tumor-bearing mice were treated with TRC253 (30 mg/kg, oral, once daily) or enzalutamide (30 mg/kg, oral, once daily) for 28 days, with the same vehicle formulation as the LNCaP model; tumor volume and body weight were monitored twice weekly, and tumor tissues were collected at the end of the experiment for pharmacodynamic analysis [1] |
| ADME/Pharmacokinetics |
1. TRC253 showed good oral bioavailability in rats (68%) and dogs (72%); the plasma half-life (t1/2) after oral administration was 4.2 hours in rats and 6.8 hours in dogs [1]
2. After oral administration of 10 mg/kg TRC253, the maximum plasma concentration (Cmax) was 1.2 μM and the area under the curve (AUC0-24h) was 8.6 μM·h in rats; in dogs, the Cmax was 0.9 μM and the AUC0-24h was 7.3 μM·h at an oral dose of 5 mg/kg [1] 3. TRC253 was widely distributed in rat tissues, with high concentrations in the prostate, liver and kidneys, and low brain permeability (brain/plasma ratio < 0.1) [1] 4. Metabolic studies have shown that TRC253 is mainly metabolized by cytochrome P450 (CYP). Enzyme metabolism, among which CYP3A4 is the main isoenzyme responsible for its metabolism [1] |
| Toxicity/Toxicokinetics |
1. The plasma protein binding rate of TRC253 in human, rat, and canine plasma was >98% [1]
2. In acute toxicity studies in rats and mice, oral doses of up to 300 mg/kg of TRC253 were well tolerated, with no deaths or obvious clinical toxic symptoms observed; in a 28-day subchronic toxicity study in rats, at doses of 10, 30, and 100 mg/kg/day, the only observed adverse reaction was a mild increase in liver enzymes in the 100 mg/kg dose group, which was reversible after drug withdrawal [1] |
| References | |
| Additional Infomation |
1. TRC253 (JNJ-63576253) is a novel, orally bioavailable selective androgen receptor antagonist for the treatment of castration-resistant prostate cancer (mCRPC), particularly mCRPC carrying the AR-F877L mutation, which confers resistance to enzalutamide [1]. 2. The mechanism of action of TRC253 involves competitive binding to the AR ligand-binding domain (LBD), inhibiting AR nuclear translocation and subsequent transcriptional activation of AR target genes (such as PSA and TMPRSS2), thereby inhibiting the proliferation of prostate cancer cells [1]. 3. TRC253 has entered the clinical development stage (Phase I/II) for the treatment of mCRPC patients carrying wild-type or F877L mutant AR [1]. 4. Enzalutamide-resistant mCRPC usually carries AR point mutations. Mutation types include F877L, and TRC253 is the first clinical-stage AR antagonist with potent activity against the AR-F877L mutant [1]
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| Molecular Formula |
C23H22CLF3N6O2S
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|---|---|
| Molecular Weight |
538.972992420197
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| Exact Mass |
538.116
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| Elemental Analysis |
C, 51.26; H, 4.11; Cl, 6.58; F, 10.57; N, 15.59; O, 5.94; S, 5.95
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| CAS # |
2110428-64-1
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| Related CAS # |
JNJ-63576253 free base;2110426-27-0
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| PubChem CID |
130229811
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| Appearance |
Off-white to light yellow solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
36
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| Complexity |
884
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QDINJYHLAKIZLE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H21F3N6O2S.ClH/c24-23(25,26)17-10-15(13-29-18(17)11-27)31-20(33)22(6-1-7-22)32(21(31)35)14-2-3-19(30-12-14)34-16-4-8-28-9-5-16;/h2-3,10,12-13,16,28H,1,4-9H2;1H
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| Chemical Name |
5-[8-oxo-5-(6-piperidin-4-yloxypyridin-3-yl)-6-sulfanylidene-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile;hydrochloride
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| Synonyms |
JNJ63576253 HCl; JNJ63576253 hydrochloride, TRC253; TRC-253; TRC 253; JNJ63576253; JNJ 63576253; JNJ 63576253;
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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: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~250 mg/mL (~463.85 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.86 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 20.8 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: ≥ 2.08 mg/mL (3.86 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 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.86 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 | 1.8554 mL | 9.2770 mL | 18.5539 mL | |
| 5 mM | 0.3711 mL | 1.8554 mL | 3.7108 mL | |
| 10 mM | 0.1855 mL | 0.9277 mL | 1.8554 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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