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K-11777 (APC-3316; K-777) is a novel, orally bioactive and irreversible cysteine protease inhibitor as well as a selective CCR4 antagonist with anticancer and antiviral activity. K777 irreversibly inhibits Cruzain which is the major cysteine protease of Trypansoma cruzi, and cathepsins B and L. Thus, K777 has a broad-spectrum antiviral activity by targeting cathepsin-mediated cell entry. K777 also inhibits SARS-CoV and EBOV pseudovirus entry with IC50 values of 0.68 nM and 0.87 nM, respectively.
| ln Vitro |
K777 (K11777) can block entry caused by various viral envelope proteins, such as filoviruses (Glycoproteins of EBOV, SUDV, TAFV, RESTV), BEBOV, and MARV, or HIV-based pseudotyped viruses with coronavirus spikes (SARS-CoV, HCoV-229E, NL63, and MERS-CoV). K777, with IC50 values of 0.68 nM, 1.48 nM, 6.78 nM, 46.12 nM, and so on, blocks the entry of SARS-CoV, HCoV-229E, NL63, MERS-CoV, EBOV, SUDV, TAFV, RESTV, BEBOV, MARV, and Nipah pseudovirus. 1,14, 2.26, 3.37, 5.91, 1.9, 0.42, 1.87, and 2.26 nM. On the other hand, alphavirus (CHIKV), rhabdovirus (VSV), flavivirus (HCV), retroviruses MLV-A and XMRV, and two arenaviruses, Lassa virus and Junin virus, were not inhibited by 100 nM K777. glycoprotein-mediated membrane infection [1]. K777 by itself demonstrated a 70% reduction in 229E-mediated transduction. When K777 and camostat were used together, the inhibition rate rose to almost 90%. The human intestinal epithelial cell line Caco-2, which expresses endogenous TMPRSS2 and cathepsins, was used to generate a comparable pattern of inhibition [1]. In Hut78 cells, K777 reduces both CCL17-induced chemotaxis and CCL17 binding (IC50 57 nM and 8.9 nM, respectively). K777-mediated chemotaxis inhibition was still effective even when CCL17 concentrations were ten times greater. K777 decreases cell surface CCR4 by around 50% and causes CCR4 internalization. K777 does not inherently trigger Ca2+ mobilization, nor does it block CXCR4-induced chemotaxis or internalization [3].
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| ln Vivo |
K777 (K11777; 35-105 mg/kg; oral dose; twice daily; for 10 days; C57BL/6 IFN-γR-KO mice) therapy protected mice from otherwise deadly infections [4].
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| Animal Protocol |
Animal/Disease Models: C57BL/6 IFN-γR-KO mice (6-8 weeks of age) injected with Cryptosporidium parvum[4]
Doses: 35 mg/kg, 70 mg/kg, and 105 mg/kg Route of Administration: Oral administration; twice a day; for 10 days Experimental Results: Rescued mice from otherwise lethal infections. |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
K-11777 has known human metabolites that include N-desmethyl k-11777, N-oxide k-11777, and b-hydroxy-homoPhe K11777. |
| References |
|
| Molecular Formula |
C32H38N4O4S
|
|---|---|
| Molecular Weight |
574.73352
|
| Exact Mass |
574.261
|
| CAS # |
233277-99-1
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| Related CAS # |
502960-90-9;
|
| PubChem CID |
9851116
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| Appearance |
White to off-white solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
41
|
| Complexity |
939
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
CN1CCN(CC1)C(=O)NC(CC2=CC=CC=C2)C(=O)NC(CCC3=CC=CC=C3)C=CS(=O)(=O)C4=CC=CC=C4
|
| InChi Key |
RHJLQMVZXQKJKB-FPHSVDBKSA-N
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| InChi Code |
InChI=1S/C32H38N4O4S/c1-35-20-22-36(23-21-35)32(38)34-30(25-27-13-7-3-8-14-27)31(37)33-28(18-17-26-11-5-2-6-12-26)19-24-41(39,40)29-15-9-4-10-16-29/h2-16,19,24,28,30H,17-18,20-23,25H2,1H3,(H,33,37)(H,34,38)/b24-19+/t28-,30-/m0/s1
|
| Chemical Name |
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]-4-methylpiperazine-1-carboxamide
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| Synonyms |
APC 3316 K-11777 K-777APC3316 K11777 K777APC-3316
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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 : ~100 mg/mL (~173.99 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.35 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 (4.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7399 mL | 8.6997 mL | 17.3995 mL | |
| 5 mM | 0.3480 mL | 1.7399 mL | 3.4799 mL | |
| 10 mM | 0.1740 mL | 0.8700 mL | 1.7399 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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