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Chemical Structure| 729-46-4 Chemical Structure| 729-46-4

Structure of JX06
CAS No.: 729-46-4

Chemical Structure| 729-46-4

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JX06 is a potent and selective covalent PDK inhibitor. It inhibits PDK1, PDK2, and PDK3 with IC50 values of 49 nM, 101 nM, and 313 nM, respectively. JX06 inhibits PDK1 activity through covalent binding with cysteine residues and exhibits antitumor activity.

Synonyms: NSC 402538

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Ittipat Meewan ; Jacob Kattoula ; Julius Y. Kattoula ; Danielle Skinner ; Pavla Fajtová ; Miriam A. Giardini , et al.

Abstract: One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC50s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.

Keywords: COVID-19 drug candidates ; multiple protease inhibitors ; disulfiram ; thiuram disulfide ; dithiobis-(thioformate) ; SARS-CoV-2 main protease ; SARS-CoV-2 papain-like protease ; cathepsin L ; transmembrane serine protease 2 TMPRSS2 ; COVID-19

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Ittipat Meewan ; Jacob Kattoula ; Julius Y. Kattoula ; Danielle Skinner ; Pavla Fajtová ; Miriam A. Giardini , et al.

Abstract: There are currently no FDA approved inhibitors of SARS-CoV-2 viral proteases with specific treatment for post-exposure of SARS-CoV-2. Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases in SARS CoV-2 replication including SARS CoV-2 Main Protease (Mpro), SARS CoV-2 Papain Like Protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by disulfiram, a currently prescribed drug commonly used to treat chronic alcoholism that at the present time is in Phase 2 clinical trials against SARS-CoV-2. At the maximal allowed dose, disulfiram is associated with adverse effects. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, JX 06, and RI172 are the most potent inhibitors from an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L with IC50s of 330, 250 nM, and 190 nM about 4.5, 17, and 11.5-fold more potent than disulfiram, respectively. The identified protease inhibitors in this series were also tested against SARS CoV-2 in a cell-based and toxicity assay and were shown to have similar or greater antiviral effect than disulfiram. The identified triple protease inhibitors and their derivatives are promising candidates for treatment of the Covid-19 virus and related variants.

Keywords: Covid19 drug candidates ; Multiple protease inhibitors ; Disulfiram ; Thiuram disulfide ; dithiobis(thioformate) ; SARS-CoV-2 Main Protease ; SARS-CoV-2 Papain Like Protease ; Cathepsin L ; Transmembrane ; Serine Protease 2 TMPRSS2 ; COVID-19

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Meewan, Ittipat ;

Abstract: Over several centuries, infectious diseases caused by viruses have been a serious threat for human health globally. Even though the numbers new highly effective antiviral drugs or vaccines have been developed for the treatment rapidly, but there are plenty of newly emerge viruses that have no proper specific treatment. In addition, the reemergence of new drug resistance viral strain is a huge challenge for drug development. This dissertation presents studies the therapeutic approach of major infectious viral diseases by proper drug target selection, design of small molecules, and test the effectiveness of small molecules experimentally. In chapter 1, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases in The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) replication including Main Protease (Mpro), SARS CoV-2 Papain Like Protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by disulfiram, a currently prescribed drug commonly used to treat chronic alcoholism that at the present time is in Phase 2 clinical trials against SARS-CoV-2. At the maximal allowed dose, disulfiram is associated with adverse effects. We found a few compounds that were more potent than disulfiram in the enzymatic assays against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L. The identified protease inhibitors in this series were also tested against SARS CoV-2 in a cell-based and toxicity assay and were shown to have similar or greater antiviral effect than Disulfiram. In chapter 2, we identified a novel transient deep and hydrophobic pocket of the “super-open” conformation of Zika virus (ZIKV) NS2B-NS3 protease and targeted it to overcome the limitations of the orthosteric inhibitors. We applied virtual docking screening of approximately 7 million compounds against the novel allosteric site and found seven candidates. Six out of seven top candidates selected by the docking screen inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations, as well as suppressing viral replication. In chapter 3, we discovered the novel class of small molecules based on a tryptophan derivative scaffold identified as hepatitis C (HCV) NS3/4A protease inhibitors that are active against both wild type and mutant form of the protease. We selected the compounds that the predicted binding poses not affected by the most frequent mutations in the active site. The top compounds had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild-type enzyme. The top three inhibitors were also tested against four human serine proteases and were shown to be specific to the viral protease. The fluorescence-based cell viability assay demonstrated a sufficient therapeutic range for the top three candidates.

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Product Details of JX06

CAS No. :729-46-4
Formula : C10H16N2O2S4
M.W : 324.51
SMILES Code : S=C(SSC(N1CCOCC1)=S)N2CCOCC2
Synonyms :
NSC 402538
MDL No. :MFCD00072237
InChI Key :KKVYOWPPMNSLCP-UHFFFAOYSA-N
Pubchem ID :12892

Safety of JX06

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H319-H372-H410
Precautionary Statements:P501-P273-P260-P270-P264-P280-P391-P314-P337+P313-P305+P351+P338-P301+P312+P330
Class:9
UN#:3077
Packing Group:

Related Pathways of JX06

PI3K-AKT

Isoform Comparison

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

3.08mL

0.62mL

0.31mL

15.41mL

3.08mL

1.54mL

30.82mL

6.16mL

3.08mL

Dissolving Methods
Please choose the appropriate dissolution scheme according to your animal administration guide.For the following dissolution schemes, clear stock solution should be prepared according to in vitro experiments, and then cosolvent should be added in turn:

in order to ensure the reliability of the experimental results, the clarified stock solution can be properly preserved according to the storage conditions; The working fluid for in vivo experiment is recommended to be prepared now and used on the same day;

The percentage shown in front of the following solvent refers to the volume ratio of the solvent in the final solution; If precipitation or precipitation occurs in the preparation process, it can be assisted by heating and/or ultrasound.
Protocol 1
Protocol 2

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