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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Targets |
KSQ-4279 targets ubiquitin-specific protease 1 (USP1), a deubiquitinating enzyme involved in DNA damage repair. It acts as an allosteric inhibitor, binding to a site distinct from the active site. By inhibiting USP1, KSQ-4279 impairs DNA repair and enhances the sensitivity of cancer cells to DNA-damaging agents, including PARP inhibitors.
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| ln Vitro |
KSQ-4279 causes S-cycle cell cycle, considerable accumulation of γ-H2A histone family member X (ϒH2AX), and enhances cell carcinogenesis in BRCA1/2 mutant breast cancer cells [1].
In vitro, KSQ-4279 inhibits USP1 with an IC50 of 21.1 nM. It exhibits anti-proliferative activity in cancer cell lines and shows synergistic activity in combination with PARP inhibitors. The compound is a potent and selective USP1 inhibitor. |
| ln Vivo |
KSQ-4279 displayed dose-dependent, strong and sustained anti-tumor regression in numerous TNBC and advanced cancer PDX models with diverse genomic state, including BRCA1 mutant and wild-type models [1].
In vivo activity data for KSQ-4279 are not extensively detailed in the available sources. The compound is orally bioavailable and is being developed for oncology research. Specific in vivo efficacy data are not provided. |
| Enzyme Assay |
The in vitro enzyme assay for KSQ-4279 involves measuring the inhibition of USP1 deubiquitinating activity. Recombinant USP1 is incubated with a ubiquitinated substrate in the presence of varying compound concentrations. The IC50 is determined by quantifying the reduction in substrate deubiquitination using techniques such as fluorescence-based or ELISA assays.
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| Cell Assay |
Cellular assays are performed using cancer cell lines. Cells are treated with KSQ-4279 alone or in combination with PARP inhibitors. Cell viability is assessed using assays such as MTT or CellTiter-Glo. Synergistic activity is evaluated using combination index analysis. DNA damage repair is assessed by measuring γH2AX foci formation.
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| Animal Protocol |
In vivo animal studies for KSQ-4279 are not detailed in the available sources. The compound is orally bioavailable and is being developed for oncology research. Specific animal models and dosing regimens are not described.
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| ADME/Pharmacokinetics |
KSQ-4279 is an orally bioavailable compound. It is being developed for oncology research. Specific PK parameters such as half-life, bioavailability, and clearance are not detailed in the available sources.
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| Toxicity/Toxicokinetics |
Toxicity data for KSQ-4279 are not reported in the available sources. As an investigational compound, it is used for research purposes only.
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| References | |
| Additional Infomation |
KSQ-4279, a USP1 inhibitor, is an orally bioavailable selective ubiquitin-specific protease 1 (USP1) inhibitor with apoptosis-inducing, tumor cell sensitivity-enhancing, and antitumor activity. After oral administration, KSQ-4279 specifically binds to and inhibits USP1 activity, thereby blocking USP1-mediated deubiquitination. This blocks the ubiquitin-proteasome degradation pathway, prevents the degradation of defective proteins, and leads to the accumulation of monoubiquitinated substrates. This induces the unfolded protein response (UPR). UPR may induce cell cycle arrest, reduce the expression of certain anti-apoptotic proteins, induce tumor cell apoptosis, inhibit tumor cell growth, and may enhance tumor cell sensitivity to DNA-targeted chemotherapy drugs. USP1 is a deubiquitinating enzyme overexpressed in various tumor cell types, playing a crucial role in the proper folding and deubiquitination of proteins and promoting DNA repair by regulating the Fanconi anemia complex and trans-damage synthesis.
KSQ-4279 is a research compound being investigated for the treatment of cancers, particularly in combination with PARP inhibitors. It is a first-in-class, selective allosteric USP1 inhibitor. The compound is available from chemical suppliers for research use only. |
| Molecular Formula |
C27H25F3N8O
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|---|---|
| Molecular Weight |
534.54
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| Exact Mass |
534.21
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| CAS # |
2446480-97-1
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| Related CAS # |
2446480-97-1;
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| PubChem CID |
150782011
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| Appearance |
White to light yellow solid powder
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| LogP |
4
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
39
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| Complexity |
823
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(C2=C(OC)N=CN=C2C2CC2)=NC=C2C=NN(CC3=CC=C(C4N(C(C)C)C=C(C(F)(F)F)N=4)C=C3)C2=N1
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| InChi Key |
KCBWAFJCKVKYHO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H25F3N8O/c1-15(2)37-13-20(27(28,29)30)35-24(37)18-6-4-16(5-7-18)12-38-25-19(11-34-38)10-31-23(36-25)21-22(17-8-9-17)32-14-33-26(21)39-3/h4-7,10-11,13-15,17H,8-9,12H2,1-3H3
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| Chemical Name |
6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine
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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 : ~80 mg/mL (~149.66 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.74 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 20.0 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 mg/mL (3.74 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 20.0 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 | 1.8708 mL | 9.3538 mL | 18.7077 mL | |
| 5 mM | 0.3742 mL | 1.8708 mL | 3.7415 mL | |
| 10 mM | 0.1871 mL | 0.9354 mL | 1.8708 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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