ALK4 inhibitors(activin A receptor type 1B inhibitors), ALK5 inhibitors(Transforming growth factor beta receptor 1 inhibitors), ALK7 inhibitors(activin A receptor type 1C inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC22H16N4O3

InChIKeyFHYUGAJXYORMHI-UHFFFAOYSA-N

CAS Registry301836-41-9

100 Clinical Results associated with SB-431542

100 Translational Medicine associated with SB-431542

100 Patents (Medical) associated with SB-431542

1,685

Literatures (Medical) associated with SB-431542

31 Dec 2025·Experimental Lung Research

Zebrafish as a model for investigating Klebsiella pneumoniae -driven lung injury and therapeutic targets

Article

Author: Ye, Jian ; Shang, Zhong-bo ; Tu, Fan ; Lu, Lei ; Liu, Jun ; Ren, Mei-di ; Rui, Xiao-hong

Background: Lung injury induced by Klebsiella pneumoniae infection presents a significant challenge, with complex molecular mechanisms driving tissue damage and immune dysregulation. This study aimed to establish a zebrafish model of K. pneumoniae-induced lung injury to explore the underlying molecular mechanisms involved in tissue damage, immune responses, and development.Methods: A zebrafish model was developed by injecting K. pneumoniae into the swim bladder at 96 h post-fertilization (hpf). The immune response, including neutrophil migration and cytokine secretion, was assessed through histological analysis and quantitative measures. Transcriptomic analysis was performed to evaluate gene expression changes related to lung development, immune regulation, and metabolism. The role of the TGF-β signaling pathway in immune response and tissue repair was investigated using the TGF-β inhibitor SB 431542.Results: Infection with K. pneumoniae induced rapid neutrophil migration and the secretion of inflammatory cytokines such as IL-6, IL-1β, TNF-α, and TNF-β, similar to immune responses seen in mouse models. Transcriptomic analysis revealed significant alterations in genes involved in lung development, immune responses, and metabolic pathways, underscoring the broad impact of infection on physiological regulation. The TGF-β signaling pathway was found to play a dual role: it promoted immune cell recruitment and cytokine secretion but suppressed developmental genes, delaying tissue repair. Treatment with SB 431542 reduced neutrophil aggregation, lowered cytokine levels, and restored gene expression related to development and repair.Conclusions: This zebrafish model effectively mimics K. pneumoniae-induced lung injury, offering valuable insights into the molecular mechanisms of tissue damage and immune dysregulation. Targeting the TGF-β signaling pathway holds therapeutic potential for reducing inflammation and promoting tissue repair, providing a foundation for the development of new treatment strategies for lung infections.

01 Jun 2025·Animal Bioscience

Key events in the process of sex determination and differentiation in early chicken embryos

Article

Author: Han, Wei ; Niu, Yingjie ; Zhu, Xilin ; Sun, Changhua ; Liu, Guanzheng ; Liu, Xin ; Song, Jiuzhou ; Qian, Hongwu ; Lv, Xiaoqian ; Sun, Hongyan ; Li, Zeyv ; Jin, Kai ; Zuo, Qisheng ; Wu, Jun ; Gong, Wei ; Chen, Guo Hong ; Li, Bichun

Objective: Current understanding of sex determination and differentiation mechanisms during early chicken embryonic development remains incomplete. To address this, we applied RNA sequencing to identify male-female expression differences at critical developmental stages (E0 blastocysts, E3.5-E6.5 genital ridges, E18.5 gonads), focusing on glycolysis, histone acetylation, and DNA methylation. This approach aims to unravel key regulatory mechanisms and advance developmental biology insights.Methods: We analyzed molecular mechanisms of chicken sex determination at key stages (E0 blastocysts, E3.5-E6.5 genital ridges, E18.5 gonads) using RNA sequencing. Glycolysis, histone acetylation, and DNA methylation levels were assessed in embryonic stem cells and chicken embryonic fibroblasts. E18.5 gonads were treated with glycolytic activators (SB431542 and PD0325901 [2i]), a DNA demethylation activator (Vitamin C [Vc]), or an inhibitors of histone acetylation modification (valproic acid [VPA]). Sex-related gene expression, hormone levels, and gonad morphology were evaluated to determine treatment effects.Results: Key findings revealed that sex differences emerged as early as the blastocyst stage, intensified with embryonic development and were marked by a surge in sexually dimorphic gene expression. Gene Ontology and Kyoto encyclopedia of genes and genomes analyses highlighted the pivotal roles of energy metabolism and epigenetic modification process during this critical period. 2i, VC, or VPA interventions targeting E18.5 embryo gonads, induced a remarkable transformation of ovarian tissue into a testis-like structure, characterized by cortical thinning, medulla densification, downregulation of female-specific genes (FOXL2, WNT4), upregulation of male-specific genes (SOX9, AMH), and increased testosterone secretion. This phenotypic and molecular shift underscores the ability of metabolic and epigenetic modulators to reprogram ovarian development towards a male-like pattern, preserving male sexual characteristics.Conclusion: Our study establishes energy metabolism and epigenetic regulation as central drivers of avian sex determination. These findings advance understanding of vertebrate developmental biology and provide a framework for dissecting regulatory networks in avian sexual development.

07 Apr 2025·Molecular Pharmaceutics

Lipopolysaccharide Induces Resistance to CAR-T Cell Therapy of Colorectal Cancer Cells through TGF-β-Mediated Stemness Enhancement

Article

Author: Zong, Chen ; Zhu, Xinyu ; Zhou, Daoyu ; Yang, Xue ; Feng, Shiyao ; Wei, Lixin ; Yan, Haixin ; Qian, Xiaofeng ; Hou, Xiaojuan ; Zhang, Li ; Tao, Min ; Zhang, Luyao ; Xue, Mengmeng

Chimeric antigen receptor-T (CAR-T) cell therapy is a cellular immunotherapy that has emerged in recent years, and increasing studies showed that therapeutic resistance to CAR-T cell therapy presents in colorectal cancer patients. Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is known to preserve a high concentration in the colon. Whether LPS is a contributing factor to the development of resistance in colorectal cancer cells against CAR-T cell therapy remains unclear. For in vivo experiments, colorectal cancer cells COLO205 were pretreated with LPS for 24 h and then were injected into nude mice through the tail vein, followed by CAR-T cells transplantation one day later. Later, the number of tumors in the lung tissues of the mice was observed. The in vitro experiments were performed on COLO205 cells, which were treated with LPS for 24 h. The effect of LPS on the stemness of COLO205 and SW620 cells was observed by using the colony formation assay and spheroidization experiments. The effect of LPS on the expression of stemness-related genes, including CD44, SOX2, and NANOG, was observed by qRT-PCR assay, Western blotting assay, and immunofluorescence staining. Inhibitors of TGF-β and the MYD88 inhibitor were used to study the mechanisms by which LPS induces the stemness enhancement and resistance to CAR-T cell therapy of COLO205 cells. The correlation between MYD88 and TGFB1, as well as the correlation between TGFB1 and stemness-related genes was analyzed using the TCGA database. Both the in vivo assay of nude mice and the in vitro assay showed that LPS pretreatment could induce resistance to CAR-T cell therapy of colorectal cancer cells. LPS could enhance COLO205 and SW620 cells stemness presented by upregulation of CD44, SOX2, and NANOG. The reverse interfering assay using the TGF-β inhibitor indicated that the autosecretion of TGF-β induced by LPS played a critical role in the stemness enhancement of colorectal cancer cells. The TCGA database analysis revealed a strong positive correlation between MYD88 and TGFB1. Additionally, TGFB1 has been found to upregulate the expression of genes associated with stemness. Further mechanism studies showed that the TLR4/MYD88 pathway medicates LPS-induced TGF-β expression. Our results suggested that LPS-induced resistance to CAR-T cell therapy of colorectal cancer cells through stemness enhancement. TLR4/MYD88 signal pathway-dependent TGF-β expression was involved in stemness enhancement and CAR-T cell therapy resistance. In conclusion, our findings help us to understand the underlying mechanisms of CAR-T cell therapy resistance and indicate that inhibitors of TGF-β and MYD88 are promising targeting candidates to promote a therapeutic effect of CAR-T cell therapy in colorectal cancer in the clinic.

100 Deals associated with SB-431542

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	GSK Plc	31 Jul 2002

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