GW788388 | GW-788388 | CAS#452342-67-5 | TGF-beta type I receptor inhibitor

MedKoo Cat#: 401488 | Name: GW788388

Description:

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

GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542. We studied its effect in vitro and found that it inhibited both the TGF-beta type I and type II receptor kinase activities, but not that of the related bone morphogenic protein type II receptor. Further, it blocked TGF-beta-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis.

Chemical Structure

GW788388

CAS#452342-67-5

Theoretical Analysis

MedKoo Cat#: 401488

Name: GW788388

CAS#: 452342-67-5

Chemical Formula: C25H23N5O2

Exact Mass: 425.1852

Molecular Weight: 425.48

Elemental Analysis: C, 70.57; H, 5.54; N, 16.46; O, 7.52

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,850.00	2 weeks
2g	USD 6,450.00	2 weeks

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Related CAS #

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Synonym

GW788388; GW-788388; GW 788388

IUPAC/Chemical Name

4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide

InChi Key

SAGZIBJAQGBRQA-UHFFFAOYSA-N

InChi Code

InChI=1S/C25H23N5O2/c31-25(29-20-9-13-32-14-10-20)18-6-4-17(5-7-18)23-15-19(8-12-27-23)21-16-28-30-24(21)22-3-1-2-11-26-22/h1-8,11-12,15-16,20H,9-10,13-14H2,(H,28,30)(H,29,31)

SMILES Code

O=C(NC1CCOCC1)C2=CC=C(C3=NC=CC(C4=CNN=C4C5=NC=CC=C5)=C3)C=C2

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, not in water

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

2934999090

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#BBC70216

QC Data

View QC data: current batch, Lot#BBC70216

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

GW788388 is a potent and selective inhibitor of ALK5 with IC50 of 18 nM in a cell-free assay.

In vitro activity:

To test the specificity of GW788388, an in vitro kinase assay was performed on full-length constitutively actively signalling receptors. Human embryonic kidney 293T cells were transiently transfected with expression plasmids encoding constitutively active ALK (caALK)5, TβRII, BMPRII, or activin type II receptor (ActRII). Receptors were immunoprecipitated and challenged with γ-32P-labelled ATP and 10 μM of compounds. GW788388 potently inhibited autophosphorylation of ALK5, TβRII, and to some extent ActRII (Figure 1b). The compound had no effect on the BMP type II receptor kinase activity. To address if GW788388 was cytotoxic, cells were treated with a dilution range of the compound and measured cell viability after 72 h. GW788388 showed no toxicity in Namru murine mammary gland (NMuMG) (Figure 1c), MDA-MB-231, renal cell carcinoma (RCC)4, and U2OS cells (data not shown) when treated with dilutions from 4 nM to 15 μM. Similar results were obtained with the SB431542 inhibitor (Figure 1c). Reference: Kidney Int. 2008 Mar;73(6):705-15. https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(15)53061-5

In vivo activity:

The db/db mouse model of spontaneous diabetic nephropathy was chosen for further in vivo characterisation of GW788388. Six-month-old mice were used, with advanced-stage renal disease, significant glomerular changes, and elevated albuminuria. Mice were treated with oral administration of 2 mg kg−1 day−1 of GW788388 for 5 weeks. No adverse side effects were observed with the treatment. Figure 7a shows diabetic mouse kidneys stained with Masson's Trichrome stain. Collagen deposits are observed in blue. Robust collagen deposits were seen in glomeruli and minimal to mild glomeropathy was evident in most diabetic animals (left panel). Treatment with GW788388 at 2 mg kg−1 day−1 resulted in a reduced collagen staining (Figure 7a, right panel). Glomerulopathy was assessed independently in picric acid stain-stained sections, scored blinded. Diabetic mice had significant glomerulopathy marked by mesangial matrix expansion, mesangial hypertrophy, proliferation, and glomerular basement membrane thickening. This was significantly reduced when treated with GW788388 (Figure 7b). Urinary albumin excretion was additionally measured and corrected for creatinine concentrations. In diabetic mice, urinary albumin levels were significantly elevated (Figure 7c). GW788388 appeared to decrease urinary albumin concentrations, although not statistically significant, suggesting that the underlying glomerular dysfunction persisted in the treated animals. To confirm that the observed changes, in glomerulopathy and the trend for reduced albuminuria, correlated with inhibition of TGF-β target genes in vivo, RNA was extracted from whole kidneys and the levels of matrix mRNAs examined. FN, COL-I, PAI-1, and COL-III expression levels were significantly increased in diabetic mice as compared with their lean littermates (Figure 7d). Treatment with 2 mg kg−1 day−1 of GW788388 significantly reduced the mRNA levels of PAI-1, COL-I, and COL-III to nearly the same levels as seen in the non-diabetic lean littermates. Taken together, these results indicate that GW788388 attenuates TGF-β signalling in vivo and effectively reduces hallmarks of fibrogenesis in mice suffering from late-stage diabetic nephropathy. Reference: Kidney Int. 2008 Mar;73(6):705-15. https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(15)53061-5

	Solvent	mg/mL	mM
Solubility
	DMSO	48.0	112.81

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 425.48 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:

In vitro protocol:

In vivo protocol:

1. Petersen M, Thorikay M, Deckers M, van Dinther M, Grygielko ET, Gellibert F, de Gouville AC, Huet S, ten Dijke P, Laping NJ. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int. 2008 Mar;73(6):705-15. doi: 10.1038/sj.ki.5002717. Epub 2007 Dec 12. PMID: 18075500. 2. Tan SM, Zhang Y, Connelly KA, Gilbert RE, Kelly DJ. Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1415-25. doi: 10.1152/ajpheart.01048.2009. Epub 2010 Feb 12. PMID: 20154262.

1: Wang Y, Jiang H, Chen Q, Guo F, Zhang B, Hu L, Huang X, Shen W, Gao J, Chen W, Xu W, Cai Z, Wei L, Li M. Myofibroblast-Targeting Extracellular Vesicles: A Promising Platform for Cardiac Fibrosis Drug Delivery. Biomater Res. 2025 Apr 11;29:0179. doi: 10.34133/bmr.0179. PMID: 40225952; PMCID: PMC11986206. 2: PLOS Neglected Tropical Diseases Editors. Retraction: Oral Administration of GW788388, an Inhibitor of Transforming Growth Factor Beta Signaling, Prevents Heart Fibrosis in Chagas Disease. PLoS Negl Trop Dis. 2024 Jul 23;18(7):e0012360. doi: 10.1371/journal.pntd.0012360. PMID: 39042593; PMCID: PMC11265650. 3: Das K, Basak M, Mahata T, Biswas S, Mukherjee S, Kumar P, Moniruzzaman M, Stewart A, Maity B. Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure. FASEB J. 2023 Aug;37(8):e23064. doi: 10.1096/fj.202300094R. PMID: 37440271. 4: Jennings P, Carta G, Singh P, da Costa Pereira D, Feher A, Dinnyes A, Exner TE, Wilmes A. Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells. Cell Biol Toxicol. 2023 Aug;39(4):1773-1793. doi: 10.1007/s10565-022-09783-5. Epub 2022 Dec 31. PMID: 36586010; PMCID: PMC10425493. 5: Grogan SP, Glembotski NE, D'Lima DD. ALK-5 Inhibitors for Efficient Derivation of Mesenchymal Stem Cells from Human Embryonic Stem Cells. Tissue Eng Part A. 2023 Mar;29(5-6):127-140. doi: 10.1089/ten.TEA.2022.0164. Epub 2023 Jan 27. PMID: 36458467. 6: Zou Q, Du X, Zhou L, Yao D, Dong Y, Jin J. A short peptide encoded by long non-coding RNA small nucleolar RNA host gene 6 promotes cell migration and epithelial-mesenchymal transition by activating transforming growth factor- beta/SMAD signaling pathway in human endometrial cells. J Obstet Gynaecol Res. 2023 Jan;49(1):232-242. doi: 10.1111/jog.15476. Epub 2022 Nov 17. PMID: 36396030. 7: Subramanian U, Ramasamy C, Ramachandran S, Oakes JM, Gardner JD, Pandey KN. Genetic Disruption of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Triggers Differential Cardiac Fibrosis and Disorders in Male and Female Mutant Mice: Role of TGF-β1/SMAD Signaling Pathway. Int J Mol Sci. 2022 Sep 29;23(19):11487. doi: 10.3390/ijms231911487. PMID: 36232788; PMCID: PMC9569686. 8: Teixeira GS, Andrade AA, Torres LR, Couto-Lima D, Moreira OC, Abreu R, Waghabi MC, de Souza EM. Suppression of TGF-β/Smad2 signaling by GW788388 enhances DENV-2 clearance in macrophages. J Med Virol. 2022 Sep;94(9):4359-4368. doi: 10.1002/jmv.27879. Epub 2022 Jun 2. PMID: 35596058; PMCID: PMC9544077. 9: Zhang Y, Li Z, He Y, Liu Y, Mi G, Chen J. T-2 toxin induces articular cartilage damage by increasing the expression of MMP-13 via the TGF-β receptor pathway. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221075555. doi: 10.1177/09603271221075555. PMID: 35213812. 10: Zhang Y, Li Z, He Y, Zhang M, Feng Y, Fang Q, Ma T, Deng X, Chen J. Transforming growth factor-β receptors mediates matrix degradation and abnormal hypertrophy in T-2 toxin-induced hypertrophic chondrocytes. Toxicon. 2022 Feb;207:13-20. doi: 10.1016/j.toxicon.2022.01.002. Epub 2022 Jan 5. PMID: 34995556. 11: Lho Y, Do JY, Heo JY, Kim AY, Kim SW, Kang SH. Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells. Int J Mol Sci. 2021 Apr 29;22(9):4739. doi: 10.3390/ijms22094739. PMID: 33947038; PMCID: PMC8124410. 12: Zhang J, Thorikay M, van der Zon G, van Dinther M, Ten Dijke P. Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells. J Vis Exp. 2020 Oct 27;(164). doi: 10.3791/61830. Erratum in: J Vis Exp. 2020 Dec 15;(166). doi: 10.3791/6453. PMID: 33191940. 13: Fang L, Zhou C, Jiang M, Li X, Liu T, Tian J, He A. Development of a ultra- performance LC-MS/MS method for quantification of GW788388 and its applications in pharmacokinetic study in rats. Bioanalysis. 2020 Dec;12(23):1681-1688. doi: 10.4155/bio-2020-0249. Epub 2020 Nov 12. PMID: 33179532. 14: Patin J, Castro C, Steenman M, Hivonnait A, Carcouët A, Tessier A, Lebreton J, Bihouée A, Donnart A, Le Marec H, Baró I, Charpentier F, Derangeon M. Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a+/- mice. Pharmacol Res. 2020 Sep;159:104922. doi: 10.1016/j.phrs.2020.104922. Epub 2020 May 25. PMID: 32464326. 15: Howe MD, Furr JW, Munshi Y, Roy-O'Reilly MA, Maniskas ME, Koellhoffer EC, d'Aigle J, Sansing LH, McCullough LD, Urayama A. Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke. Geroscience. 2019 Oct;41(5):543-559. doi: 10.1007/s11357-019-00118-7. Epub 2019 Nov 13. PMID: 31721012; PMCID: PMC6885082. 16: Chen Y, Wang N, Yuan Q, Qin J, Hu G, Li Q, Tao L, Xie Y, Peng Z. The Protective Effect of Fluorofenidone against Cyclosporine A-Induced Nephrotoxicity. Kidney Blood Press Res. 2019;44(4):656-668. doi: 10.1159/000500924. Epub 2019 Aug 6. PMID: 31387101. 17: Ferreira RR, Abreu RDS, Vilar-Pereira G, Degrave W, Meuser-Batista M, Ferreira NVC, da Cruz Moreira O, da Silva Gomes NL, Mello de Souza E, Ramos IP, Bailly S, Feige JJ, Lannes-Vieira J, de Araújo-Jorge TC, Waghabi MC. TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. PLoS Negl Trop Dis. 2019 Jul 31;13(7):e0007602. doi: 10.1371/journal.pntd.0007602. PMID: 31365537; PMCID: PMC6690554. 18: Levolger S, Wiemer EAC, van Vugt JLA, Huisman SA, van Vledder MG, van Damme- van Engel S, Ambagtsheer G, IJzermans JNM, de Bruin RWF. Inhibition of activin- like kinase 4/5 attenuates cancer cachexia associated muscle wasting. Sci Rep. 2019 Jul 8;9(1):9826. doi: 10.1038/s41598-019-46178-9. PMID: 31285507; PMCID: PMC6614551. 19: McMillin M, Grant S, Frampton G, Petrescu AD, Williams E, Jefferson B, DeMorrow S. The TGFβ1 Receptor Antagonist GW788388 Reduces JNK Activation and Protects Against Acetaminophen Hepatotoxicity in Mice. Toxicol Sci. 2019 May 1;170(2):549-561. doi: 10.1093/toxsci/kfz122. PMID: 31132129; PMCID: PMC6821297. 20: McMillin M, Grant S, Frampton G, Petrescu AD, Williams E, Jefferson B, Thomas A, Brahmaroutu A, DeMorrow S. Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice. J Neuroinflammation. 2019 Apr 2;16(1):69. doi: 10.1186/s12974-019-1455-y. PMID: 30940161; PMCID: PMC6446280.