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Purity: ≥98%
HG-9-91-01 (HG9-91-01) is a novel, potent and highly selective inhibitor of salt-inducible kinase (SIKs) with antidiabetic effects. It inhibits SIK1/2/3 with IC50s of 0.92 nM, 6.6 nM and 9.6 nM, respectively. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver.
| ln Vitro |
Many protein tyrosine kinases containing threonine residues at gatekeeping regions, including BTK, FGF and Ephrin receptors, Yes, Lck, and Src family members, are inhibited by HG-9-91-01 [1]. HG-9-91-01 revealed a robust association between increased IL-10 production and SIK2 inhibitory efficacy. In line with these findings, pretreatment of BMDC with a number of other kinases and the recently reported SIK1-3 inhibitor HG-9-91-01 led to a concentration-dependent increase in zymosan-induced IL-10 production, with an EC50~200 nM maximum effect that is comparable to that seen for PGE2 [2]. HG-9-91-01 exhibited over 100-fold more potency against SIK in cell-free tests compared to AMPK (IC50=4.5 μM). Pck1 and G6pc mRNA expression was dose-dependently raised by HG-9-91-01 treatment, and the result was comparable to that of cells treated with 4 μM HG-9-91-01. Additionally, after receiving HG-9-91-01 therapy, there was a dose-dependent increase in glucose production, which is consistent with this observation [3].
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| References |
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| Additional Infomation |
HG-9-91-01 is a member of the class of phenylureas that is a potent inhibitor of salt-inducible kinase 2, a potential target protein for therapy in ovarian cancer. It has a role as an antineoplastic agent and a salt-inducible kinase 2 inhibitor. It is a dimethoxybenzene, an aminopyrimidine, a N-arylpiperazine, a N-alkylpiperazine, a secondary amino compound and a member of phenylureas.
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| Molecular Formula |
C32H37N7O3
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| Molecular Weight |
567.6813
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| Exact Mass |
567.295
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| CAS # |
1456858-58-4
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| PubChem CID |
78357808
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| Appearance |
White to yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
779.7±70.0 °C at 760 mmHg
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| Flash Point |
425.3±35.7 °C
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| Vapour Pressure |
0.0±2.8 mmHg at 25°C
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| Index of Refraction |
1.630
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| LogP |
4.57
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
42
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| Complexity |
825
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
UYUHRKLITDJEHB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H37N7O3/c1-22-7-6-8-23(2)31(22)36-32(40)39(27-14-13-26(41-4)19-28(27)42-5)30-20-29(33-21-34-30)35-24-9-11-25(12-10-24)38-17-15-37(3)16-18-38/h6-14,19-21H,15-18H2,1-5H3,(H,36,40)(H,33,34,35)
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| Chemical Name |
1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-1-[6-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]urea
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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 : ≥ 150 mg/mL (~264.23 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.40 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.66 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.66 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 | 1.7616 mL | 8.8078 mL | 17.6156 mL | |
| 5 mM | 0.3523 mL | 1.7616 mL | 3.5231 mL | |
| 10 mM | 0.1762 mL | 0.8808 mL | 1.7616 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.
 The SIK inhibitor HG-9-91-01 increases hepatic gluconeogenesis.Nat Commun.2014 Aug 4;5:4535. |
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 Effect of HG-9-91-01 in AMPK- or LKB1-knockout primary hepatocytes.Nat Commun.2014 Aug 4;5:4535. |
 An SIK2 drug-resistant mutant prevented the effects of HG-9-91-01. |
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