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| 10mg |
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| Targets |
KL201 selectively targets cryptochrome 1 (CRY1), a core component of the circadian clock. It binds to the FAD-binding pocket of CRY1, preventing its interaction with FBXL3 and ubiquitin-dependent degradation. KL201 does not stabilize CRY2, demonstrating isoform selectivity. By stabilizing CRY1, KL201 enhances its activity and modulates the expression of clock-controlled genes involved in metabolism, hormone regulation, and cellular homeostasis. The compound's selective targeting of CRY1 over CRY2 makes it a valuable tool for dissecting the distinct roles of these two cryptochrome isoforms in circadian biology.
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| ln Vitro |
In cells containing the circadian reporter Bmal1-dLuc as well as the other circadian reporter Per2-dLuc, KL201 results in a dose-dependent prolongation of the circadian period. KL201 significantly reduces Per2-dLuc reporter intensity compared to Bmal1-dLuc, all while maintaining cellular viability[1]. KL201 binds to CRY1 in an overlap with FBXL3, a ubiquitin ligase complex subunit, and FBXL3 knockdown attenuates KL201's effect[1]. In mouse lung primary explants, KL201 prolonged the circadian period and reduced the intensity of the Per2::Luc knockin reporter[1].
KL201 lengthens the period of circadian rhythms in cells and tissues. In cell-based circadian chemical screening, KL201 was identified as a compound that significantly extended the circadian period. The compound's activity has been demonstrated in various cellular models, showing its ability to modulate circadian oscillations. KL201 enhances ovarian function by reducing ferritinophagy. These in vitro studies confirm KL201's role as a CRY1 stabilizer and circadian period modulator, providing a basis for its use in chronobiology research and therapeutic development for clock-related disorders. |
| ln Vivo |
In vivo studies have demonstrated that administration of KL201 significantly alleviates anxiety-like behavior in male mice. Cry1 ablation triggered innate and stress-induced anxiety-like behavior, whereas activation of CRY1 by KL201 alleviated anxiety-like behavior in mice. These findings suggest that KL201's CRY1-stabilizing activity has behavioral effects in animal models. The compound's ability to modulate circadian rhythms in vivo makes it a promising candidate for studying the link between circadian clock disruption and mood disorders, as well as for developing chronobiology-based therapeutics.
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| Enzyme Assay |
The in vitro enzyme/receptor binding assay for KL201 involves assessing its binding to CRY1 and CRY2 proteins. The compound's selectivity for CRY1 is evaluated by measuring its binding affinity to the FAD-binding pocket of CRY1. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be used to determine binding kinetics and thermodynamics. Competition binding assays with FBXL3 are performed to confirm that KL201 prevents the CRY1-FBXL3 interaction. These assays are typically conducted using purified recombinant CRY1 and CRY2 proteins in buffer systems optimized for protein-protein interaction studies, with readouts including binding affinity (Kd) and inhibition of FBXL3 binding.
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| Cell Assay |
In vitro cellular assays for KL201 typically use cell lines expressing circadian reporter genes, such as fibroblasts with a luminescent circadian reporter. Cells are treated with KL201 at various concentrations, and circadian period length is monitored over several days using real-time bioluminescence recording. The compound's effect on circadian period is quantified by analyzing the oscillation patterns. Additionally, CRY1 protein levels are measured by Western blot to confirm stabilization. Cellular viability and cytotoxicity are assessed using standard assays like MTT or CellTiter-Glo to ensure that the observed circadian effects are not due to non-specific toxicity.
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| Animal Protocol |
In vivo animal experiments with KL201 typically use mouse models to study circadian rhythm modulation and behavioral effects. Male mice are administered KL201 via intraperitoneal injection or oral gavage. Circadian rhythms are monitored using locomotor activity tracking under controlled light-dark cycles. Behavioral assays, such as elevated plus maze and open field tests, are conducted to assess anxiety-like behavior. Tissue samples are collected for analysis of CRY1 protein levels and clock gene expression. Pharmacodynamic studies measure the compound's effects on circadian period and behavior.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of KL201 are not extensively documented in available literature. As a small-molecule modulator with a molecular weight of 388.28, KL201 is expected to have reasonable oral bioavailability and tissue distribution, consistent with typical drug-like compounds. Its mechanism of action involves binding to the FAD-binding pocket of CRY1, suggesting that the compound can access intracellular targets. Further pharmacokinetic studies, including assessments of absorption, distribution, metabolism, and excretion (ADME), are necessary to fully characterize its PK profile and support its development as a therapeutic agent for clock-related diseases.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for KL201 is not available in the public domain. As a research compound used primarily for in vitro and in vivo studies, KL201 has not undergone extensive toxicological evaluation. Standard cytotoxicity assays in cell lines have likely been performed to establish safe concentration ranges for cellular experiments. In animal studies, tolerability and potential adverse effects are typically monitored, but detailed toxicity profiles are not published. Further preclinical toxicology studies would be required to assess safety, determine no-observed-adverse-effect levels (NOAEL), and evaluate potential off-target effects before clinical development.
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| References | |
| Additional Infomation |
KL201 is a thienopyrimidine derivative identified as a CRY1-selective stabilizer through cell-based circadian chemical screening. It binds to the FAD-binding pocket of CRY1, preventing FBXL3 interaction and ubiquitin-dependent degradation. KL201 lengthens circadian period in cells and tissues and alleviates anxiety-like behavior in male mice. The compound is a valuable tool for chronobiology research and therapeutic development for clock-related diseases. KL201 has a molecular weight of 388.28 and formula C17H14BrN3OS. It is available as a high-purity research compound for non-clinical use. No clinical trials or regulatory approvals have been reported for KL201.
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| Molecular Formula |
C17H14BRN3OS
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| Molecular Weight |
388.281561374664
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| Exact Mass |
387.004
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| CAS # |
302939-48-6
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| PubChem CID |
1330855
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| Appearance |
White to yellow solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
23
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| Complexity |
452
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| Defined Atom Stereocenter Count |
0
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| SMILES |
BrC1C=CC=CC=1C(NC1=C2C(=NC=N1)SC1CCCCC=12)=O
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| InChi Key |
KFSLRFWIPVMBNT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H14BrN3OS/c18-12-7-3-1-5-10(12)16(22)21-15-14-11-6-2-4-8-13(11)23-17(14)20-9-19-15/h1,3,5,7,9H,2,4,6,8H2,(H,19,20,21,22)
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| Chemical Name |
2-bromo-N-(5,6,7,8-tetrahydro-[1]benzothiolo[2,3-d]pyrimidin-4-yl)benzamide
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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: 250 mg/mL (643.87 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.36 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 20.8 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 | 2.5755 mL | 12.8773 mL | 25.7546 mL | |
| 5 mM | 0.5151 mL | 2.5755 mL | 5.1509 mL | |
| 10 mM | 0.2575 mL | 1.2877 mL | 2.5755 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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