A 83-01

A 83-01 is a potent and selective small-molecule inhibitor of TGF-β type I receptors ALK5, ALK4, and ALK7 (IC₅₀=12nM, 45nM, 7.5nM). A 83-01 competitively binds to the ATP site of the ALK kinase domain, blocks Smad2/3 phosphorylation, inhibits TGF-β/Smad signaling, and suppresses epithelial-mesenchymal transition (EMT) and fibrosis processes. A 83-01 can be used in stem cell reprogramming and pluripotency maintenance, organoid culture, and studies related to EMT, fibrosis, and cancer metastasis^[1-4].

In vitro, in an LPS-induced Caco-2/RAW264.7 co-culture inflammatory model, A 83-01 (2μM; 24h) downregulated TGF-β1 and SMAD4 transcription levels, inhibited phosphorylation of p-SMAD2/3, p-AKT, and p-RPS6, upregulated LncGAS5 and LncCDKN2B expression, prevented EMT initiation in inflamed intestinal epithelium, and protected epithelial barrier integrity^[5]. A 83-01 (500nM; 2 days) inhibited IFN-γ-, LPS-, TNF-α-, and IL-1β-induced p38 phosphorylation in adipose tissue-derived stem cells and upregulated TSG-6 expression^[6]. Treatment of SK-OV-3 and OVCAR-3 cells incubated with platelets using A 83-01 (25μM) for 24-48h inhibited platelet-induced pSmad2 elevation and invasion enhancement, and reversed platelet-triggered EMT-like changes^[7].

In vivo, a single intraperitoneal injection of A 83-01 (1mg/kg) in colon 26 tumor-bearing mice induced tumor vascular normalization, increased pericyte coverage, and enhanced vascular permeability^[8]. Intraperitoneal injection of A 83-01 (150μg/mouse; three times per week; continuous treatment until death) in an HM-1 mouse ovarian cancer peritoneal dissemination model slowed ascites accumulation, inhibited ovarian cancer peritoneal dissemination, and significantly prolonged mouse survival^[9]. Starting from the day after left anterior descending coronary artery ligation myocardial infarction surgery in Nkx2.5 enhancer-GFP transgenic mice, intraperitoneal injection of A 83-01 (10mg/kg) for 7 consecutive days expanded the cardiac Nkx2.5+ cardiomyoblast population, increased lineage-traced newly generated cardiomyocyte numbers, and improved systolic function parameters such as ventricular elastance^[10].

References:

[1] Tojo M, Hamashima Y, Hanyu A, et al. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005 Nov;96(11):791-800.

[2] Taniguchi Y, Kawano K, Minowa T, et al. Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor. Cancer Sci. 2010 Oct;101(10):2207-13.

[3] Sun X, Kim YH, Phan TN, et al. Topical application of ALK5 inhibitor A-83-01 reduces burn wound contraction in rats by suppressing myofibroblast population. Biosci Biotechnol Biochem. 2014;78(11):1805-12.

[4] Cui X, Shang S, Lv X, et al. Perspectives of small molecule inhibitors of activin receptor‑like kinase in anti‑tumor treatment and stem cell differentiation (Review). Mol Med Rep. 2019 Jun;19(6):5053-5062.

[5] Ghorbaninejad M, Abdollahpour-Alitappeh M, Shahrokh S, et al. TGF-β receptor I inhibitor may restrict the induction of EMT in inflamed intestinal epithelial cells. Exp Biol Med (Maywood). 2023 Apr;248:665-676.

[6] Kwon H Y, Yoon Y, Hong J-E, et al. Role of TGF-β and p38 MAPK in TSG-6 Expression in Adipose Tissue-Derived Stem Cells In Vitro and In Vivo. Int J Mol Sci. 2024 Jan;25(1):477.

[7] Guo Y, Cui W, Pei Y, et al. Platelets promote invasion and induce epithelial to mesenchymal transition in ovarian cancer cells by TGF-β signaling pathway. Gynecol Oncol. 2019 Sep;153(3):639-650.

[8] Minowa T, Kawano K, Kuribayashi H, et al. Increase in tumour permeability following TGF-β type I receptor-inhibitor treatment observed by dynamic contrast-enhanced MRI. Br J Cancer. 2009 Nov;101(11):1884-1890.

[9] Yamamura S, Matsumura N, Mandai M, et al. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer. 2012;130(1):20-28.

[10] Chen W P, Liu Y H, Ho Y J, et al. Pharmacological inhibition of TGFB receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res. 2015;105:44-54.