HG-9-91-01
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Hodoodo CAT#: H561501

CAS#: 1456858-58-4

Description: HG-9-91-01 is a potent and highly selective salt-inducible kinase (SIKs) inhibitor for SIK1, SIK2 and SIK3. Inhibition of SIK kinase activity induces an anti-inflammatory phenotype in macrophages.


Chemical Structure

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HG-9-91-01
CAS# 1456858-58-4

Theoretical Analysis

Hodoodo Cat#: H561501
Name: HG-9-91-01
CAS#: 1456858-58-4
Chemical Formula: C32H37N7O3
Exact Mass: 567.30
Molecular Weight: 567.690
Elemental Analysis: C, 67.70; H, 6.57; N, 17.27; O, 8.45

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 450 Ready to ship
50mg USD 750 Ready to ship
100mg USD 1250 Ready to ship
200mg USD 2150 Ready to ship
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Synonym: HG-9-91-01; HG-9-91-01; HG 9-91-01; HG9-91-01; HG99101; HG-99101; HG 99101;

IUPAC/Chemical Name: 1-(2,4-Dimethoxyphenyl)-3-(2,6-dimethylphenyl)-1-(6-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)urea

InChi Key: UYUHRKLITDJEHB-UHFFFAOYSA-N

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)

SMILES Code: O=C(NC1=C(C)C=CC=C1C)N(C2=CC=C(OC)C=C2OC)C3=NC=NC(NC4=CC=C(N5CCN(C)CC5)C=C4)=C3

Appearance: Solid powder

Purity: >95% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: HG-9-91-01 is a potent and highly selective salt-inducible kinase (SIK) inhibitor with IC50s of 0.92 nM, 6.6 nM and 9.6 nM for SIK1, SIK2 and SIK3 respectively.
In vitro activity: In this study, the expression and function of SIK (selective salt-inducible kinase) in human myeloid cells by use of 2 structurally unrelated SIK inhibitors (HG-9-91-01 and ARN-3236) and an RNAi approach was analylzed. The SIK inhibitor HG-9-91-01 possesses a very good selectivity profile against the other members of the AMPK family and a good selectivity against the kinome. Initially, the effect of the SIK inhibitor in the mouse RAW264.7 cells was analyzed (Supplemental Fig. 2A). HG-9-91-01 inhibited LPS-induced secretion of TNF-α with an IC50 of 267 nM, while showing no signs of cellular toxicity up to a concentration of 10 μM (Supplemental Fig. 2A). One hour pretreatment with HG-9-91-01 significantly blocked TLR4 (LPS)- and TLR2 (Pam3CSK4)induced TNF-α production while increasing at the same time IL-10 secretion in BMDM (Supplemental Fig. 3A) and BMDC (Supplemental Fig. 3B). Pretreatment with HG-9-91-01 markedly reduced TNF-α production in human monocytes and macrophages, stimulated with LPS (Fig. 1B) or Pam3CSK4 (Fig. 1C). HG-9-91-01 pretreatment significantly decreased CXCL9 and CD80 mRNA levels (Fig. 3A). However, the data suggests that the macrophage phenotype after SIK inhibition is not completely immunosuppressive, as some levels of IL-6 and IL-1β are maintained, as shown for “regulatory-like macrophages” J Leukoc Biol. 2016 May;99(5):711-21. https://pubmed.ncbi.nlm.nih.gov/26590148/
In vivo activity: In this study, the effects and underlying mechanism of HG-9-91-01 in murine colitis models were investigated. The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium-induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice. Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01-treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01. It was found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy. Inflamm Bowel Dis. 2021 May 14;izab072. https://pubmed.ncbi.nlm.nih.gov/33988718/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 85.0 148.66

Preparing Stock Solutions

The following data is based on the product molecular weight 567.69 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Lombardi MS, Gilliéron C, Dietrich D, Gabay C. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. J Leukoc Biol. 2016 May;99(5):711-21. doi: 10.1189/jlb.2A0715-307R. Epub 2015 Nov 20. PMID: 26590148. 2. Wang C, Song D, Fu J, Wen X. SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells. Front Endocrinol (Lausanne). 2020 Sep 2;11:580. doi: 10.3389/fendo.2020.00580. PMID: 33013689; PMCID: PMC7493656 3. Fu Y, Ma G, Zhang Y, Wang W, Shi T, Zhu J, Zhang J, Huang Z, Chen J. HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway. Inflamm Bowel Dis. 2021 May 14:izab072. doi: 10.1093/ibd/izab072. Epub ahead of print. PMID: 33988718. 4. Patel K, Foretz M, Marion A, Campbell DG, Gourlay R, Boudaba N, Tournier E, Titchenell P, Peggie M, Deak M, Wan M, Kaestner KH, Göransson O, Viollet B, Gray NS, Birnbaum MJ, Sutherland C, Sakamoto K. The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nat Commun. 2014 Aug 4;5:4535. doi: 10.1038/ncomms5535. PMID: 25088745; PMCID: PMC4143937.
In vitro protocol: 1. Lombardi MS, Gilliéron C, Dietrich D, Gabay C. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. J Leukoc Biol. 2016 May;99(5):711-21. doi: 10.1189/jlb.2A0715-307R. Epub 2015 Nov 20. PMID: 26590148. 2. Wang C, Song D, Fu J, Wen X. SIK1 Regulates CRTC2-Mediated Gluconeogenesis Signaling Pathway in Human and Mouse Liver Cells. Front Endocrinol (Lausanne). 2020 Sep 2;11:580. doi: 10.3389/fendo.2020.00580. PMID: 33013689; PMCID: PMC7493656
In vivo protocol: 1. Fu Y, Ma G, Zhang Y, Wang W, Shi T, Zhu J, Zhang J, Huang Z, Chen J. HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway. Inflamm Bowel Dis. 2021 May 14:izab072. doi: 10.1093/ibd/izab072. Epub ahead of print. PMID: 33988718. 2. Patel K, Foretz M, Marion A, Campbell DG, Gourlay R, Boudaba N, Tournier E, Titchenell P, Peggie M, Deak M, Wan M, Kaestner KH, Göransson O, Viollet B, Gray NS, Birnbaum MJ, Sutherland C, Sakamoto K. The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nat Commun. 2014 Aug 4;5:4535. doi: 10.1038/ncomms5535. PMID: 25088745; PMCID: PMC4143937.

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1: Lombardi MS, Gilliéron C, Berkelaar M, Gabay C. Salt-inducible kinases (SIK) inhibition reduces RANKL-induced osteoclastogenesis. PLoS One. 2017 Oct 3;12(10):e0185426. doi: 10.1371/journal.pone.0185426. eCollection 2017. PubMed PMID: 28973003.

2: Darling NJ, Toth R, Arthur JS, Clark K. Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. Biochem J. 2017 Feb 15;474(4):521-537. doi: 10.1042/BCJ20160646. Epub 2016 Dec 5. PubMed PMID: 27920213; PubMed Central PMCID: PMC5290485.

3: Säll J, Pettersson AM, Björk C, Henriksson E, Wasserstrom S, Linder W, Zhou Y, Hansson O, Andersson DP, Ekelund M, Degerman E, Stenkula KG, Laurencikiene J, Göransson O. Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals: implications for insulin signalling and glucose uptake in human adipocytes. Diabetologia. 2017 Feb;60(2):314-323. doi: 10.1007/s00125-016-4141-y. Epub 2016 Nov 2. PubMed PMID: 27807598.

4: Sundberg TB, Liang Y, Wu H, Choi HG, Kim ND, Sim T, Johannessen L, Petrone A, Khor B, Graham DB, Latorre IJ, Phillips AJ, Schreiber SL, Perez J, Shamji AF, Gray NS, Xavier RJ. Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo. ACS Chem Biol. 2016 Aug 19;11(8):2105-11. doi: 10.1021/acschembio.6b00217. Epub 2016 Jun 6. PubMed PMID: 27224444; PubMed Central PMCID: PMC4992440.

5: Lombardi MS, Gilliéron C, Dietrich D, Gabay C. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. J Leukoc Biol. 2016 May;99(5):711-21. doi: 10.1189/jlb.2A0715-307R. Epub 2015 Nov 20. PubMed PMID: 26590148.

6: Sundberg TB, Choi HG, Song JH, Russell CN, Hussain MM, Graham DB, Khor B, Gagnon J, O'Connell DJ, Narayan K, Dančík V, Perez JR, Reinecker HC, Gray NS, Schreiber SL, Xavier RJ, Shamji AF. Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells. Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12468-73. doi: 10.1073/pnas.1412308111. Epub 2014 Aug 11. PubMed PMID: 25114223; PubMed Central PMCID: PMC4151730.

7: Patel K, Foretz M, Marion A, Campbell DG, Gourlay R, Boudaba N, Tournier E, Titchenell P, Peggie M, Deak M, Wan M, Kaestner KH, Göransson O, Viollet B, Gray NS, Birnbaum MJ, Sutherland C, Sakamoto K. The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nat Commun. 2014 Aug 4;5:4535. doi: 10.1038/ncomms5535. PubMed PMID: 25088745; PubMed Central PMCID: PMC4143937.

8: Norman P. The use of salt-inducible kinase inhibitors to treat autoimmune and inflammatory diseases: evaluation of WO2013136070. Expert Opin Ther Pat. 2014 Aug;24(8):943-6. doi: 10.1517/13543776.2014.908851. Epub 2014 Apr 19. PubMed PMID: 24745372.

9: Clark K, MacKenzie KF, Petkevicius K, Kristariyanto Y, Zhang J, Choi HG, Peggie M, Plater L, Pedrioli PG, McIver E, Gray NS, Arthur JS, Cohen P. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91. doi: 10.1073/pnas.1215450109. Epub 2012 Oct 2. PubMed PMID: 23033494; PubMed Central PMCID: PMC3479463.