Inhibition of HTR2B-mediated serotonin signaling in colorectal cancer suppresses tumor growth through ERK signaling.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Serotonin (5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system and as a paracrine, exocrine, or endocrine messenger in peripheral tissues. In this study, we hypothesized that inhibition of serotonin signaling using 5-HT receptor 2B (HTR2B) inhibitors could potentially impede the progression of CRC. We treated CT26 and COLO-205 cells with SB204741, an inhibitor of HTR2B, and evaluated CRC cell proliferation and migration. We then evaluated the effects of HTR2B inhibition in a xenograft mouse model of human colorectal cancer. We also evaluated the role of a novel inhibitor, GM-60186, using both in vitro and in vivo models. RNA sequencing analysis was performed to elucidate the underlying mechanism of the anti-tumor effects of pharmacological inhibition of HTR2B on CRC. In both CRC cell lines and xenograft mouse models, we show that pharmacological inhibition of HTR2B with SB204741 and GM-60186 significantly inhibits CRC cell proliferation and migration. HTR2B inhibition leads to the suppression of extracellular signal-regulated kinase (ERK) signaling, a critical pathway in CRC pathogenesis. Notably, transcriptomic analysis reveals distinct gene expression changes associated with HTR2B inhibition, providing insight into its therapeutic potential. In this study, we found that pharmacological inhibition of HTR2B suppressed CRC proliferation via ERK signaling. In addition, we proposed a novel HTR2B inhibitor for the treatment of CRC. This study highlights the potential role of HTR2B signaling in CRC. These inhibitors may contribute to new therapeutics for CRC treatment.

Discovery of novel arylpyridine derivatives for motile ciliogenesis.

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies.

Design, Synthesis, and Biological Evaluation of New 2,6,7-Substituted Purine Derivatives as Toll-like Receptor 7 Agonists for Intranasal Vaccine Adjuvants.

TLR7/8 agonists are versatile immune stimulators capable of treating various diseases such as viral infections, autoimmune, and cancer. Despite the structural similarity of TLR7/8, their immune stimulation mechanisms and time-course responses significantly differ. In this study, a new series of TLR7-selective agonists was synthesized utilizing the economical building block 2,6-dichloropurine. Compound 27b showed the most potent activity on hTLR7 with an EC50 of 17.53 nM and demonstrated high hTLR7 selectivity (224 folds against TLR8). 27b effectively stimulated the secretion of proinflammatory cytokines in mouse macrophages and enhanced intranasal vaccine efficacy against influenza A virus in vivo. Assessment of humoral and mucosal antibody titers confirmed that 27b elevates IgG and IgA levels, protecting against both homologous and heterologous influenza viral infections. These findings suggest that 27b is a promising candidate as a vaccine adjuvant to prevent viral infections or as a robust immunomodulator with prolonged activity for treating immune-suppressed diseases.

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Identification of new arylsulfide derivatives as anti-melanogenic agents in a zebrafish model.

A series of aryl sulfide derivatives was synthesized and evaluated for their anti-melanogenic activities. Several compounds, including 3e, 3i and 3q exhibited good anti-melanogenic activities. Among the derivatives, compound 3i showed good inhibitory effects against melanin synthesis and showed no toxicity in reconstituted human eye and skin tissues.