| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
ATR ( IC50 = 0.013 μM )
SKLB-197 targets ATR (ATM and Rad3-related protein kinase), a key regulator of the DNA damage response (DDR) pathway. ATR is activated in response to replication stress and DNA damage, particularly single-strand breaks and stalled replication forks. It plays a critical role in maintaining genomic stability by activating cell cycle checkpoints, promoting DNA repair, and regulating replication fork progression. Cancer cells with deficiencies in ATM, another DDR kinase, are particularly sensitive to ATR inhibition due to synthetic lethality. SKLB-197's exceptional selectivity for ATR over other kinases makes it a valuable tool for studying ATR-specific functions in the DNA damage response. |
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| ln Vitro |
SKLB-197 demonstrates potent in vitro activity against ATR with an IC50 of 0.013 μM (13 nM). The compound shows minimal or no activity against 402 other protein kinases (IC50s > 1 μM), confirming its high selectivity for ATR. In cellular assays, SKLB-197 reduces growth in cancer cell lines deficient in ATM kinase with IC50s of 0.13-0.66 μM to a greater extent than in ATM-expressing cancer cell lines. This differential activity demonstrates the compound's potential for synthetic lethality-based cancer therapy in ATM-deficient tumors. SKLB-197's potent and selective ATR inhibition makes it a valuable tool for studying the role of ATR in the DNA damage response and cancer biology.
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| ln Vivo |
SKLB-197 displays potent antitumor activity against ATM-deficient tumors in vivo. The compound is orally bioavailable, making it suitable for oral administration in animal studies. In preclinical models, SKLB-197 has demonstrated efficacy in suppressing tumor growth in ATM-deficient cancer models. The compound's selectivity for ATR and its synthetic lethality with ATM deficiency provide a rationale for its use in treating cancers with ATM mutations or deficiencies. Detailed in vivo efficacy data, including specific tumor growth inhibition rates and dosing regimens, are available in the primary literature. SKLB-197 is a valuable tool for validating ATR as a therapeutic target in ATM-deficient cancers.
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| Enzyme Assay |
The in vitro enzyme inhibition assay for SKLB-197 measures the inhibition of ATR kinase activity. Recombinant human ATR enzyme is incubated with varying concentrations of SKLB-197 (typically ranging from nanomolar to micromolar) in the presence of ATP and a peptide substrate. The kinase reaction is allowed to proceed for a fixed period, and the extent of substrate phosphorylation is quantified using techniques such as fluorescence polarization, luminescence-based kinase assays, or radiometric measurement. The IC50 value of 0.013 μM is determined by fitting dose-response curves to the inhibition data. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations. Selectivity is assessed by testing the compound against a panel of 402 kinases. Appropriate positive controls and negative controls are included in each assay run.
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| Cell Assay |
The in vitro cellular assay for SKLB-197 is performed using cancer cell lines with varying ATM status, including ATM-deficient and ATM-expressing cell lines. Cells are cultured in appropriate medium and treated with varying concentrations of SKLB-197 or vehicle control (DMSO) for specified time points. Cell viability and proliferation are assessed using assays such as MTT, CellTiter-Glo, or colony formation assays. The differential sensitivity of ATM-deficient cells (IC50s = 0.13-0.66 μM) compared to ATM-expressing cells is evaluated to confirm the synthetic lethality mechanism. Additionally, the effects of SKLB-197 on ATR downstream signaling, including CHK1 phosphorylation and cell cycle checkpoints, can be assessed by Western blotting using phospho-specific antibodies.
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| Animal Protocol |
In vivo animal experiments with SKLB-197 are conducted using immunocompromised mice bearing ATM-deficient human tumor xenografts. Tumor cells are implanted subcutaneously into the flank of nude or SCID mice. When tumors reach a predetermined size, animals are randomized into treatment groups receiving SKLB-197 or vehicle control. SKLB-197 is administered orally due to its oral bioavailability. Tumor volume is measured twice weekly using calipers, and body weight is monitored to assess tolerability. At study endpoint, tumors are harvested for analysis of ATR target engagement, downstream signaling, and markers of DNA damage and apoptosis. The compound's antitumor efficacy is evaluated by comparing tumor growth in treated versus control groups.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) parameters for SKLB-197 are not extensively documented in publicly available sources. However, SKLB-197 is described as orally bioavailable, indicating that it has adequate oral absorption for in vivo studies. The compound has a molecular weight of 424.50 and a chemical formula of C25H24N6O. SKLB-197 is soluble in DMSO at 85 mg/mL (200.23 mM) but is insoluble in water and ethanol. For in vivo oral administration, the compound can be formulated as a homogeneous suspension in CMC-Na at ≥5 mg/mL. The compound should be stored at -20°C for long-term stability. Detailed PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are available in the primary literature and should be consulted for specific experimental planning.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for SKLB-197 are not extensively documented in publicly available sources. As a research-grade compound, SKLB-197 is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation. Comprehensive toxicological profiling (e.g., LD50, maximum tolerated dose, organ-specific toxicity) is not available from the current search results and would require consultation of the primary literature or safety data sheets.
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| References | |
| Additional Infomation |
SKLB-197 is a research compound developed for studying the role of ATR in the DNA damage response and for validating ATR as a therapeutic target in ATM-deficient cancers. The compound's exceptional selectivity for ATR over 402 other kinases (IC50 = 0.013 μM vs. >1 μM for others) makes it a valuable tool for dissecting ATR-specific functions in the DNA damage response. SKLB-197's synthetic lethality with ATM deficiency provides a rationale for its use in treating cancers with ATM mutations or deficiencies. The compound is not currently in clinical trials nor approved for therapeutic use; it remains an investigational tool compound for preclinical cancer research. SKLB-197 is available from various chemical suppliers for research purposes. Its utility lies in its ability to selectively inhibit ATR and probe its role in DNA damage response and synthetic lethality.
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| Molecular Formula |
C25H24N6O
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|---|---|
| Molecular Weight |
424.50
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| Exact Mass |
424.2
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| Elemental Analysis |
C, 70.73; H, 5.70; N, 19.80; O, 3.77
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| CAS # |
2713577-16-1
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| PubChem CID |
162641668
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| Appearance |
White to light yellow solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
32
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| Complexity |
650
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@H]1COCCN1C2=NC(=NC3=C2C=C(C=C3)C4=CC=NN4C)C5=C6C=CNC6=CC=C5
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| InChi Key |
FCNFJRRMUAOHKI-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C25H24N6O/c1-16-15-32-13-12-31(16)25-20-14-17(23-9-11-27-30(23)2)6-7-22(20)28-24(29-25)19-4-3-5-21-18(19)8-10-26-21/h3-11,14,16,26H,12-13,15H2,1-2H3/t16-/m1/s1
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| Chemical Name |
(3R)-4-[2-(1H-indol-4-yl)-6-(2-methylpyrazol-3-yl)quinazolin-4-yl]-3-methylmorpholine
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| Synonyms |
SKLB 197; SKLB-197; SKLB197
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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: 85~100 mg/mL (200.2~235.6 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.89 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3557 mL | 11.7786 mL | 23.5571 mL | |
| 5 mM | 0.4711 mL | 2.3557 mL | 4.7114 mL | |
| 10 mM | 0.2356 mL | 1.1779 mL | 2.3557 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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