SIS3| SMA3 inhibitor | CAS#1009104-85-1

MedKoo Cat#: 407168 | Name: SIS3

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

SMAD3 is a receptor-regulated intracellular protein that functions downstream of TGF-β and activin receptors and mediates their signaling, playing a role in cell proliferation, differentiation, apoptosis and formation of extracellular matrix. Smad3 Inhibitor, SIS3 is a cell-permeable pyrrolopyridine compound that selectively inhibits TGF-β1-dependent Smad3 phosphorylation and Smad3-mediated cellular signaling with no effect on Smad2, p38 MAPK, ERK, or PI 3-K signaling. It has been shown to reduce TGF-β1-induced type 1 procollagen expression and myofibroblast differentiation in normal dermal fibroblasts as well as scleroderma fibroblasts.

Chemical Structure

SIS3

CAS#1009104-85-1

Theoretical Analysis

MedKoo Cat#: 407168

Name: SIS3

CAS#: 1009104-85-1

Chemical Formula: C28H27N3O3

Exact Mass: 453.2052

Molecular Weight: 453.54

Elemental Analysis: C, 74.15; H, 6.00; N, 9.27; O, 10.58

Price and Availability

Size	Price	Availability	Quantity
1mg	USD 420.00	2 Weeks
5mg	USD 850.00	2 Weeks

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Synonym

1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3-(1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-propen-1-one; Specific Inhibitor of Smad3; SIS-3; SIS 3; SMAD3 Inhibitor, SIS3

IUPAC/Chemical Name

1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3-(1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-propen-1-one

InChi Key

IJYPHMXWKKKHGT-VAWYXSNFSA-N

InChi Code

InChI=1S/C28H27N3O3/c1-30-27(19-8-5-4-6-9-19)22(23-10-7-14-29-28(23)30)11-12-26(32)31-15-13-20-16-24(33-2)25(34-3)17-21(20)18-31/h4-12,14,16-17H,13,15,18H2,1-3H3/b12-11+

SMILES Code

COC1=CC(CCN(C(/C=C/C2=C(C3=CC=CC=C3)N(C)C4=C2C=CC=N4)=O)C5)=C5C=C1OC

Appearance

Solid powder

Purity

>98% (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, DMF, and ethanol

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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

SIS3 selectively inhibits TGF-β and activin signaling by suppressing Smad3 phosphorylation (IC50 = 3 µM) without affecting the MAPK/p38, ERK, or PI3-kinase signaling pathways. It has been shown to reduce TGF-β1-induced type 1 procollagen expression and myofibroblast differentiation in normal dermal fibroblasts as well as scleroderma fibroblasts.

In vitro activity:

This study proposes repurposing SIS3 as a potent modulator of ABCB1 and ABCG2 for overcoming multidrug resistance (MDR) in cancer cells. In cancer cell lines, SIS3 effectively inhibits the transport function of ABCB1 and ABCG2, enhances drug-induced apoptosis, and resensitizes MDR cancer cells to chemotherapy at non-toxic concentrations. Combining SIS3 with standard chemotherapeutic agents may offer a promising strategy for patients with MDR tumors. Reference: Cancer Lett. 2018 Oct 1;433:259-272. https://pubmed.ncbi.nlm.nih.gov/30026175/

In vivo activity:

SIS3 may serve as a promising treatment for chronic obstructive sialadenitis. SIS3 protected duct-ligated submandibular glands (SMGs) against fibrosis and dysfunction by inhibiting the TGF-β/SMAD3 signaling and inflammatory cytokine expression in micewith ligated dominant duct in SMG. Reference: J Dent Sci. 2023 Apr;18(2):865-871. https://pubmed.ncbi.nlm.nih.gov/37021213/

	Solvent	mg/mL	mM
Solubility
	DMF	30.0	66.15
	DMSO	30.0	66.15
	Ethanol	30.0	66.15

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 453.54 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.

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. Huang Z, Zhang C, Zhu K, Hu J, Xu E, Ma X, Wang Y, Zhu Y, Zhu J. (E)-SIS3 suppressed osteosarcoma progression via promoting cell apoptosis, arresting cell cycle, and regulating the tumor immune microenvironment. Drug Dev Res. 2023 Dec;84(8):1751-1763. doi: 10.1002/ddr.22120. Epub 2023 Oct 2. PMID: 37784254. 2. Wu CP, Murakami M, Hsiao SH, Liu TC, Yeh N, Li YQ, Hung TH, Wu YS, Ambudkar SV. SIS3, a specific inhibitor of Smad3 reverses ABCB1- and ABCG2-mediated multidrug resistance in cancer cell lines. Cancer Lett. 2018 Oct 1;433:259-272. doi: 10.1016/j.canlet.2018.07.004. Epub 2018 Jul 6. PMID: 30026175; PMCID: PMC6084781. 3. Li H, Wang G, Hu M, Dai R, Li C, Cao Y. Specific inhibitor of Smad3 (SIS3) alleviated submandibular gland fibrosis and dysfunction after dominant duct ligation in mice. J Dent Sci. 2023 Apr;18(2):865-871. doi: 10.1016/j.jds.2023.02.004. Epub 2023 Feb 16. PMID: 37021213; PMCID: PMC10068496. 4. Pan W, Zheng L, Gao J, Ye L, Chen Z, Liu S, Pan B, Fang J, Lai H, Zhang Y, Ni K, Lou C, He D. SIS3 suppresses osteoclastogenesis and ameliorates bone loss in ovariectomized mice by modulating Nox4-dependent reactive oxygen species. Biochem Pharmacol. 2022 Jan;195:114846. doi: 10.1016/j.bcp.2021.114846. Epub 2021 Nov 18. PMID: 34801525.

In vitro protocol:

In vivo protocol:

1. Li H, Wang G, Hu M, Dai R, Li C, Cao Y. Specific inhibitor of Smad3 (SIS3) alleviated submandibular gland fibrosis and dysfunction after dominant duct ligation in mice. J Dent Sci. 2023 Apr;18(2):865-871. doi: 10.1016/j.jds.2023.02.004. Epub 2023 Feb 16. PMID: 37021213; PMCID: PMC10068496. 2. Pan W, Zheng L, Gao J, Ye L, Chen Z, Liu S, Pan B, Fang J, Lai H, Zhang Y, Ni K, Lou C, He D. SIS3 suppresses osteoclastogenesis and ameliorates bone loss in ovariectomized mice by modulating Nox4-dependent reactive oxygen species. Biochem Pharmacol. 2022 Jan;195:114846. doi: 10.1016/j.bcp.2021.114846. Epub 2021 Nov 18. PMID: 34801525.

1: Li LF, Lee CS, Liu YY, Chang CH, Lin CW, Chiu LC, Kao KC, Chen NH, Yang CT. Activation of Src-dependent Smad3 signaling mediates the neutrophilic inflammation and oxidative stress in hyperoxia-augmented ventilator-induced lung injury. Respir Res. 2015 Sep 16;16(1):112. doi: 10.1186/s12931-015-0275-6. PubMed PMID: 26377087; PubMed Central PMCID: PMC4574227. 2: Li J, Xiong J, Yang B, Zhou Q, Wu Y, Luo H, Zhou H, Liu N, Li Y, Song Z, Zheng Q. Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial-Mesenchymal Transition to Promote Transplant Arteriosclerosis. Am J Transplant. 2015 Aug 4. doi: 10.1111/ajt.13406. [Epub ahead of print] PubMed PMID: 26372910. 3: Sundararaj K, Pleasant DL, Moschella PC, Panneerselvam K, Balasubramanian S, Kuppuswamy D. mTOR Complexes Repress Hypertrophic Agonist-Stimulated Expression of Connective Tissue Growth Factor in Adult Cardiac Muscle Cells. J Cardiovasc Pharmacol. 2015 Sep 14. [Epub ahead of print] PubMed PMID: 26371948. 4: Zhu Y, Tao H, Jin C, Liu Y, Lu X, Hu X, Wang X. Transforming growth factor β1 induces type II collagen and aggrecan expression via activation of extracellular signal regulated kinase 1/2 and Smad2/3 signaling pathways. Mol Med Rep. 2015 Oct;12(4):5573-9. doi: 10.3892/mmr.2015.4068. Epub 2015 Jul 9. PubMed PMID: 26165845. 5: Deng X, Jin K, Li Y, Gu W, Liu M, Zhou L. Platelet-Derived Growth Factor and Transforming Growth Factor β1 Regulate ARDS-Associated Lung Fibrosis Through Distinct Signaling Pathways. Cell Physiol Biochem. 2015;36(3):937-46. doi: 10.1159/000430268. Epub 2015 Jun 12. PubMed PMID: 26088859. 6: Wang Z, Xu W, Rong A, Lin Y, Qiu XL, Qu S, Lan XH. Neovibsanin B increases extracellular matrix proteins in optic nerve head cells via activation of Smad signalling pathway. Int J Clin Exp Pathol. 2015 Mar 1;8(3):3395-403. eCollection 2015. PubMed PMID: 26045877; PubMed Central PMCID: PMC4440186. 7: Yang H, Zhan L, Yang T, Wang L, Li C, Zhao J, Lei Z, Li X, Zhang HT. Ski prevents TGF-β-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer. Oncol Rep. 2015 Jul;34(1):87-94. doi: 10.3892/or.2015.3961. Epub 2015 May 7. PubMed PMID: 25955797. 8: Sun YB, Qu X, Howard V, Dai L, Jiang X, Ren Y, Fu P, Puelles VG, Nikolic-Paterson DJ, Caruana G, Bertram JF, Sleeman MW, Li J. Smad3 deficiency protects mice from obesity-induced podocyte injury that precedes insulin resistance. Kidney Int. 2015 Aug;88(2):286-98. doi: 10.1038/ki.2015.121. Epub 2015 May 6. PubMed PMID: 25945408. 9: Yamamoto N, Otsuka T, Kondo A, Matsushima-Nishiwaki R, Kuroyanagi G, Kozawa O, Tokuda H. Rac limits TGF-β-induced VEGF synthesis in osteoblasts. Mol Cell Endocrinol. 2015 Apr 15;405:35-41. doi: 10.1016/j.mce.2015.02.002. Epub 2015 Feb 7. PubMed PMID: 25662279. 10: Li L, Yin Q, Tang X, Bai L, Zhang J, Gou S, Zhu H, Cheng J, Fu P, Liu F. C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway. PLoS One. 2014 Nov 25;9(11):e113639. doi: 10.1371/journal.pone.0113639. eCollection 2014. PubMed PMID: 25422985; PubMed Central PMCID: PMC4244104.