ZLC491
Based on 1 Customer Validation
ZLC491 is an orally active PROTAC degrader that selectively targets CDK12/CDK13 and exhibits certain oral bioavailability. ZLC491 induces cereblon- and proteasome-dependent selective degradation of CDK12 and CDK13. ZLC491 inhibits the transcription and expression of long genes, and mainly acts on a subset of DNA damage response genes. ZLC491 inhibits the proliferation of various triple-negative breast cancer cells. ZLC491 can be used in research related to triple-negative breast cancer.
(Pink: CDK12 and CDK13 ligand (HY-168163); Blue: Cereblon ligand (HY-W093272); Black: linker (HY-W904851)).
For research use only. We do not sell to patients.
- Purity : 98.51%
- CAS No.: 3053716-46-1
- Formula: C48H51FN10O5
- Molecular Weight:866.98
-
Storage:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
-
Biological Activity
-
Chemical Information
-
Solvent & Solubility
- Protocols
- Purity & Documentation
- References
-
Help & FAQs
All PROTACs Isoforms
More
Biological Activity
Description
IC50 & Target
|
Cereblon |
CDK12 |
CDK13 |
In Vitro
ZLC491 selectively inhibits the proliferation of triple-negative breast cancer (TNBC) cell lines MDA-MB-231, HCC38 and MDA-MB-436, with IC50 values of 0.62, 0.19 and 0.12 μM after 5 days of treatment, respectively. It exerts a synergistic effect when combined with Cisplatin (HY-17394) or Olaparib (HY-10162). Meanwhile, ZLC491 shows extremely low activity against non-cancer cell lines[1].
ZLC491 (0.01-3 μM; 4-15 h) degrades CDK12 and CDK13 in MDA-MB-231 cells in a dose- and time-dependent manner, with a DC50 of 32 nM and 28 nM, respectively[1].
ZLC491 (0.1-0.5 μM; 48 h) dose-dependently reduces the protein levels of DDR-related proteins ATM, BRCA1 and RAD51 in MDA-MB-231 cells[1].
ZLC491 (60-300 nM; 12 h) potently and concentration-dependently inhibits the transcription of DDR genes in MDA-MB-231 cells, with no significant effect on the non-target gene ROR1[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
-
Cell Line:HCC38, MDA-MB-436
-
Concentration:0.01-3 μM
-
Incubation Time:15 h
-
Result:Concentration-dependently depleted CDK12 and CDK13 protein levels in both HCC38 and MDA-MB-436 cells, with robust degradation observed at concentrations ≥0.1 μM.
-
Cell Line:MDA-MB-231
-
Concentration:0.1-0.5 μM
-
Incubation Time:48 h
-
Result:Dose-dependently reduced protein levels of DDR-associated proteins ATM, BRCA1, and RAD51, concurrent with degradation of CDK12 and CDK13. Nearly eliminated CDK13 protein levels and significantly reduced ATM, BRCA1, and RAD51 levels relative to DMSO control at 0.5 μM.
-
Cell Line:MDA-MB-231
-
Concentration:60-300 nM
-
Incubation Time:12 h
-
Result:Concentration-dependently suppressed transcription of DDR genes including ATM, ATR, BRCA1, BRCA2, FANCD2, and SMARCC. Showed no significant effect on the control gene ROR1. Reduced ATM, ATR, BRCA1, BRCA2, and FANCD2 mRNA levels to ≤20% of DMSO control at 300 nM.
-
Cell Line:MDA-MB-231
-
Concentration:0.3-7.5 μM (in combination with cisplatin or olaparib)
-
Incubation Time:5 days
-
Result:Demonstrated strong synergistic antiproliferative activity with cisplatin, with CI values of 0.17 for 1.5 μM ZLC491 + 25 μM cisplatin and 0.07 for 7.5 μM ZLC491 + 25 μM cisplatin.
Showed additive to synergistic activity with olaparib, with CI values of 0.90 for 1.5 μM ZLC491 + 25 μM Olaparib and 0.85 for 7.5 μM ZLC491 + 25 μM Olaparib.
Parmacokinetics
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
-
Animal Model:CB17SCID mice with Triple-negative breast cancer (female, 6−8 weeks old, orthotopic xenograft model)[1]
-
Dosage:100 mg/kg; 200 mg/kg
-
Administration:p.o.; daily; 5 consecutive days
-
Result:Significantly reduced tumor CDK12 and CDK13 protein levels relative to vehicle control at 100 mg/kg.
Achieved an even greater reduction in tumor CDK12 and CDK13 protein levels at 200 mg/kg.
Induced marked tumor cell apoptosis with a histology score of ~15 (vs. ~3 for vehicle) at 200 mg/kg.
Caused no body weight loss in treated mice.
Chemical Information
-
CAS No. 3053716-46-1
-
Appearance Solid
-
Molecular Weight 866.98
-
Formula C48H51FN10O5
-
Color Light yellow to yellow
-
SMILES
O=C(N([C@@H]1CC[C@H](CC1)NC2=CC=C(C=N2)C#N)C3=CC=C(C=C3)N4CCN(CC4)C5CCN(CC5)C6=CC7=C(C=C6F)C(N(C7=O)C8CCC(NC8=O)=O)=O)NCC9=CC=CC=C9
-
Shipping
Room temperature in continental US; may vary elsewhere.
-
Storage
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvent & Solubility
In Vitro:
DMSO : 100 mg/mL (115.34 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
In Vivo:
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (2.88 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
-
-
-
-
Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
-
%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
-
%+
-
+%Tween-80 + +
-
%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Protocols
-
RNA extraction experimental
By lysing cells, releasing RNA, and removing impurities such as proteins and DNA, high-purity RNA products are finally obtained. The commonly used traditional method is the guanidine isothiocyanate/phenol/chloroform method (Trizol), which is suitable for a variety of animal materials including animal tissues, microorganisms, cultured cells, etc., and most plant materials.
-
Protocol for Pharmacokinetic Study
Pharmacokinetic studies quantify how an organism handles a drug over time through absorption, distribution, metabolism, and excretion, and the core experimental readout is the concentration-time profile of parent drug and, when relevant, metabolites in biological matrices such as plasma, whole blood, urine, bile, or tissue. Pharmacokinetic analysis links dose, route, exposure, clearance, half-life, distribution, bioavailability, and systemic exposure to drug efficacy and toxicity hypotheses rather than measuring a signaling pathway directly. The literature links pharmacokinetics to drug-development phenotypes by showing that drug metabolism and pharmacokinetics influence compound progression, exposure-response interpretation, safety margins, dosing strategy, and failure risk during discovery and development. DMPK science contributes to compound optimization by integrating physicochemical properties, in vitro metabolism, transporter behavior, in vivo exposure, and pharmacodynamic contex
-
Breast Cancer Modeling
Breast cancer is a heterogeneous cancer, and it has been distinguished into four subtypes: luminal A, luminal B, HER2-positive and basal-like. Molecular mutations, epigenetic alterations, hormone exposure and immune microenvironment are related to the progression of breast cancer.
-
Genotoxicity/Mutagenicity Study
The bacterial reverse mutation assay detects point mutations that restore amino-acid prototrophy in auxotrophic Salmonella typhimurium or Escherichia coli tester strains; after exposure to a test article, mutagenic activity is read out as an increased number of revertant colonies on minimal agar compared with the vehicle control. The assay uses tester strains with different mutation targets so that base-substitution and frameshift mutagens can be detected, and testing is performed with and without exogenous mammalian metabolic activation because some chemicals require biotransformation to become mutagenic.
-
Cell Viability Determination by MTT Colorimetric Assay
The following protocol uses the MTT colorimetric assay as a classic literature-established method for assessing cell viability/metabolic activity in cultured mammalian cells. MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] is reduced by metabolically active cells to a colored formazan product; the amount of formazan is quantified spectrophotometrically and provides an indirect measure of metabolically active viable cells. Importantly, MTT reduction reflects cellular oxidoreductase/metabolic activity rather than an absolute direct count of living cells, so changes in cellular metabolism can alter the signal independently of cell number.
Purity & Documentation
-
Data Sheet (277 KB)
-
SDS (251 KB)
- English - EN (251 KB)
- Français - FR (251 KB)
- Deutsch - DE (251 KB)
- Norwegian - NO (251 KB)
- Español - ES (251 KB)
- Swedish - SV (251 KB)
- Italian - IT (251 KB)
- Korean - KR (251 KB)
- Portuguese - PT (251 KB)
-
Handling Instructions (2659 KB)
References
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 1.1534 mL | 5.7671 mL | 11.5343 mL | 28.8357 mL |
| 5 mM | 0.2307 mL | 1.1534 mL | 2.3069 mL | 5.7671 mL | |
| 10 mM | 0.1153 mL | 0.5767 mL | 1.1534 mL | 2.8836 mL | |
| 15 mM | 0.0769 mL | 0.3845 mL | 0.7690 mL | 1.9224 mL | |
| 20 mM | 0.0577 mL | 0.2884 mL | 0.5767 mL | 1.4418 mL | |
| 25 mM | 0.0461 mL | 0.2307 mL | 0.4614 mL | 1.1534 mL | |
| 30 mM | 0.0384 mL | 0.1922 mL | 0.3845 mL | 0.9612 mL | |
| 40 mM | 0.0288 mL | 0.1442 mL | 0.2884 mL | 0.7209 mL | |
| 50 mM | 0.0231 mL | 0.1153 mL | 0.2307 mL | 0.5767 mL | |
| 60 mM | 0.0192 mL | 0.0961 mL | 0.1922 mL | 0.4806 mL | |
| 80 mM | 0.0144 mL | 0.0721 mL | 0.1442 mL | 0.3604 mL | |
| 100 mM | 0.0115 mL | 0.0577 mL | 0.1153 mL | 0.2884 mL |
ZLC491 Related Classifications
HY-168162 Related Classifications
Powered by Bioz