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LYN-1604 diHCl, the dihydrochloride salt of LYN1604, is an activator/agonist of the UNC-51-like kinase 1 (ULK1) (EC50 = 18.94 nM) with anticancer activity. ULK1 is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. LYN-1604 interacts with three amino acid residues (LYS50, LEU53, and TYR89) in the activation site of ULK1 as monitored by site-directed mutagenesis and biochemical assays. LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy.
| ln Vitro |
LYN-1604 exhibits potential as an agonist of ULK1 (enzyme activity at 100 nM = 195.7%, IC50 against MDA-MB-231 cells = 1.66 μM) [1]. With an affinity for binding in the nanomolar range (KD=291.4 nM), LYN-1604 binds to wild-type ULK1 [1]. Via the ULK complex, LYN-1604 (0.5, 1.0, and 2.0 μM) causes cell death in MDA-MB-231 cells [1]. In MDA-MB-231 cells, LYN-1604 (0.5-2 μM, 24 hours) leads to a notable increase of Beclin-1, p62 degradation, and the conversion of LC3-I to LC3-II [1]. Via the ULK complex, LYN-1604 triggers autophagy that is ATG5-dependent [1]. Additionally, LYN-1604 has the ability to trigger apoptosis and promote caspase3 cleavage [1].
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| ln Vivo |
LYN-1604 dihydrochloride, administered intragastrically once daily for 14 days at low, middle, and high doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg, inhibited the growth of xenografted TNBC by targeting ULK1 and modulating cell death [1].
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: MDA-MB-231 cells Tested Concentrations: 0.5, 1.0 and 2.0 μM Incubation Duration: Experimental Results: Induced cell death. Autophagy ratio was increased in a dose-dependent manner. Western Blot Analysis[1] Cell Types: MDA-MB-231 cells Tested Concentrations: 0, 0.5, 1, and 2 μM Incubation Duration: 24 hrs (hours) Experimental Results: Induced remarkable up-regulation of Beclin-1 and degradation of p62, as well as transformation of LC3-I to LC3 -II. |
| Animal Protocol |
Animal/Disease Models: 24 female nude mice (BALB/c, 6-8 weeks, 20-22 g)[1]
Doses: Low dose, 25 mg/kg; median dose, 50 mg/kg; high dose, 100 mg/kg Route of Administration: intragastric (po) administration; one time/day for 14 days Experimental Results: Dramatically inhibited the growth of xenograft MDA-MB-231 cells. The body weights of mice were stable. By the end of the experiment, the liver and spleen weight indexes of mice were slightly increased in parts of the groups, while the kidney weight index was not affected in all dose groups. |
| References |
| Molecular Formula |
C33H45CL4N3O2
|
|---|---|
| Molecular Weight |
657.541305303574
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| Exact Mass |
657.223
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| CAS # |
2310109-38-5
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| Related CAS # |
LYN-1604;2088939-99-3;LYN-1604 hydrochloride;2216753-86-3
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| PubChem CID |
131954512
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
42
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| Complexity |
750
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=C(C=CC=1C(CN1CCN(C(CN(CC(C)C)CC(C)C)=O)CC1)OCC1C=CC2C=CC=CC=2C=1)Cl.Cl.Cl
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| InChi Key |
GZCBLOPFZPJUOQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H43Cl2N3O2.2ClH/c1-24(2)19-37(20-25(3)4)22-33(39)38-15-13-36(14-16-38)21-32(30-12-11-29(34)18-31(30)35)40-23-26-9-10-27-7-5-6-8-28(27)17-26;;/h5-12,17-18,24-25,32H,13-16,19-23H2,1-4H3;2*1H
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| Chemical Name |
2-[bis(2-methylpropyl)amino]-1-[4-[2-(2,4-dichlorophenyl)-2-(naphthalen-2-ylmethoxy)ethyl]piperazin-1-yl]ethanone;dihydrochloride
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| Synonyms |
LYN1604 diHCl LYN 1604 diHCl
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
H2O : ~50 mg/mL (~76.04 mM)
DMSO : ~50 mg/mL (~76.04 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.80 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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.80 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 25.0 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 | 1.5208 mL | 7.6041 mL | 15.2082 mL | |
| 5 mM | 0.3042 mL | 1.5208 mL | 3.0416 mL | |
| 10 mM | 0.1521 mL | 0.7604 mL | 1.5208 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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