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| Targets |
Gumelutamide is a potent, selective androgen receptor (AR) pure antagonist. It targets the AR with high affinity, showing Ki values of 7.39 nM for the wild-type AR and 23.8 nM for the AR T878A mutant. It acts as a pure antagonist by inhibiting AR transcriptional activity without any residual agonist effect.
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| ln Vitro |
In vitro, Gumelutamide is a potent AR antagonist. It not only inhibits AR transcriptional activity but also effectively downregulates the protein levels of both AR-full length (AR-FL) and AR splice variants (AR-Vs). This unique dual mechanism of antagonism and degradation contributes to its high potency and ability to overcome resistance.
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| ln Vivo |
In vivo, Gumelutamide is an androgen antagonist with antineoplastic activity. By combining pure antagonism with the downregulation of AR-FL and AR-Vs, it represents a promising strategy for treating castration-resistant prostate cancer (CRPC) that has become resistant to standard-of-care AR antagonists.
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| Enzyme Assay |
Cellular AR binding assays are performed using a radioligand competition format. LNCaP cells expressing AR are incubated with a high-affinity radiolabeled androgen (e.g., [3H]-R1881) and varying concentrations of Gumelutamide. The cells are harvested, and the bound radioligand is measured by scintillation counting to calculate the Ki for displacement.
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| Cell Assay |
Cellular assays are performed in LNCaP (wild-type AR) and 22Rv1 (AR-V7 expressing) prostate cancer cell lines. Cells are seeded and treated with Gumelutamide for 24 hours. To assess transcriptional activity, cells are transfected with a PSA-luciferase reporter and treated with dihydrotestosterone (DHT). Luminescence is measured. For protein downregulation, Western blot is performed for AR-FL and AR-V7.
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| Animal Protocol |
In vivo efficacy is evaluated in xenograft mouse models of prostate cancer, including models of enzalutamide resistance. Gumelutamide is administered via oral gavage. Tumor volumes are measured with calipers. At study termination, tumors are harvested for analysis of AR-FL and AR-V7 protein levels by Western blot to confirm the in vivo downregulation mechanism.
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| ADME/Pharmacokinetics |
The pharmacokinetic (PK) profile of Gumelutamide is designed to support oral administration. Its favorable properties allow for systemic exposure that can achieve therapeutic concentrations in target tissues. Studies are ongoing to fully characterize its absorption, distribution, metabolism, and excretion.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies have been conducted to support Gumelutamide‘s development as a research agent. As a pure AR antagonist, its safety profile is expected to be manageable. No significant off-target toxicities have been reported, and its unique mechanism may offer advantages over older agents in terms of side effects.
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| References | |
| Additional Infomation |
Gumelutamide is a small molecule drug. The international nonproprietary name stem "-lutamide" in its name indicates that gumelutamide is a nonsteroidal anti-androgen. The monoisotopic molecular weight of gumelutamide is 420.15 Da.
Gumelutamide (also known as TAS3681) is a research compound that represents a new class of antiandrogens combining antagonism with downregulation. It is not approved for clinical use. Its molecular formula is C22H21ClN6O and its molecular weight is 420.89. It serves as a powerful tool for validating dual mechanism approaches to treat therapy-resistant prostate cancers. |
| Molecular Formula |
C22H21CLN6O
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|---|---|
| Molecular Weight |
420.89474272728
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| Exact Mass |
420.146
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| CAS # |
1831085-48-3
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| PubChem CID |
102004291
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
638
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(#N)C1=CC=C(N2CC3C(CC2)=C(NC2=NC=C(C(O)(C)C)C=C2)N=CN=3)C=C1Cl
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| InChi Key |
TYOPGJVWUJIKHX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21ClN6O/c1-22(2,30)15-4-6-20(25-11-15)28-21-17-7-8-29(12-19(17)26-13-27-21)16-5-3-14(10-24)18(23)9-16/h3-6,9,11,13,30H,7-8,12H2,1-2H3,(H,25,26,27,28)
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| Chemical Name |
2-chloro-4-[4-[[5-(2-hydroxypropan-2-yl)pyridin-2-yl]amino]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]benzonitrile
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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 (118.80 mM)
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3759 mL | 11.8796 mL | 23.7592 mL | |
| 5 mM | 0.4752 mL | 2.3759 mL | 4.7518 mL | |
| 10 mM | 0.2376 mL | 1.1880 mL | 2.3759 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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