From High-Throughput Screening to Target Validation: Benzo[<i>d</i>]isothiazoles as Potent and Selective Agonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 5 Possessing In Vivo Gastrointestinal Prokinetic Activity in Rodents

Barilli, Alessio; Aldegheri, Laura; Bianchi, Federica; Brault, Laurent; Brodbeck, Daniela; Castelletti, Laura; Feriani, Aldo; Lingard, Iain; Myers, Richard A.; Nola, Selena; Piccoli, Laura; Pompilio, Daniela; Raveglia, Luca F.; Salvagno, Cristian; Tassini, Sabrina; Virginio, Caterina; Sabat, Mark

doi:10.1021/acs.jmedchem.1c00065

Cited by 10 publications

(5 citation statements)

References 43 publications

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“…In human colonic cancer cells (HT29-18N2), TRPM5 channels have the potential as pharmacological targets for managing mucus-associated pathologies, such as cystic fibrosis [46], given their roles in regulating Ca 2+mediated mucin 2 and MUC5AC secretion [47]. TRPM5 agonists have shown promise in promoting rodent gastrointestinal prokinetic activity [48]. High TRPM5 mRNA expression has been associated with poor OS in both gastric cancer and melanoma patients [49].…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

HU,

WARTMANN,

STRECKER

et al. 2024

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Transient receptor potential (TRP) channels are strongly associated with colon cancer development and progression. This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature, with further validation of signature in real world samples from our hospital treated patient samples. Kaplan-Meier (K-M) survival analysis and receiver operating characteristic (ROC) curves were employed to evaluate this gene signature's predictive accuracy and robustness in both training and testing cohorts, respectively. Additionally, the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature's immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature's potential in predicting chemotherapy outcomes. The findings unveiled a novel three TRP channels-related gene signature (MCOLN1, TRPM5, and TRPV4) in colon adenocarcinoma (COAD). The ROC and K-M survival curves in the training dataset (AUC = 0.761; p = 1.58e-05) and testing dataset (AUC = 0.699; p = 0.004) showed the signature's robust predictive capability for the overall survival of COAD patients. Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration, especially an increased presence of M2 macrophages, in high-risk group patients compared to their low-risk counterparts. High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy, evident through increased CD86 and PD-1 expression profiles. Moreover, the TRPM5 gene within the signature was highly expressed in the chemoresistance group (p = 0.00095) and associated with poor prognosis (p = 0.036) in COAD patients, highlighting its role as a hub gene of chemoresistance. Ultimately, this signature emerged as an independent prognosis factor for COAD patients (p = 6.48e-06) and expression of model gene are validated by public data and real-world patients. Overall, this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer. Abbreviations COADColon adenocarcinoma TRP Transient receptor potential K-M Kaplan-Meier AUC Area under the curve ROC Receiver operating characteristic ICIImmune checkpoint inhibitor

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Section: Discussionmentioning

confidence: 99%

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

HU,

WARTMANN,

STRECKER

et al. 2024

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“…3 ) and that represent novel chemical matter to be utilized as starting points for hit-to-lead activities. Several potential hit series were identified, the hits were then clustered and further prioritized based on the calculated properties to give 16 chemical series, which were further explored by confirming the activity from solid samples and performing structure-activity relationship (SAR) expansion as recently described in Barilli et al [26] . Improved potency, selectivity and DMPK profiles would allow their use as in vitro and in vivo tool compounds to better understand the physiological and pathological roles of TRPM5 channels.…”

Section: Discussionmentioning

confidence: 99%

Identification of positive modulators of TRPM5 channel from a high-throughput screen using a fluorescent membrane potential assay

et al. 2022

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“…Next, we tried a chemogenetic approach with Gq-or Gi-coupled receptors that respond only to synthetic ligands (DREADDs) 59 Finally, we decided to stimulate TRPM5 directly, since all tuft cell chemosensing pathways identified to date converge on TRPM5. We acquired a TRPM5 agonist compound called Class 8 (C8), 61,62 and found that it induced ion flux in both the pSI and dSI when administered lumenally or basolaterally, with a trend toward higher basolateral responses (Fig. 2K, S2P-Q).…”

Section: A Trpm5 Agonist Induces Tuft-and Ach-dependent Fluid Secreti...mentioning

confidence: 99%

Tuft cell-derived acetylcholine regulates epithelial fluid secretion

Billipp

Fung

Webeck

et al. 2023

Preprint

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Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown. Here we show that tuft cell chemosensing in the intestine leads to release of ACh, but that this does not contribute to immune cell activation or associated tissue remodeling. Instead, tuft cell-derived ACh triggers immediate fluid secretion from neighboring epithelial cells into the intestinal lumen. This tuft cell-regulated fluid secretion is amplified during Type 2 inflammation, and helminth clearance is delayed in mice lacking tuft cell ACh. The coupling of the chemosensory function of tuft cells with fluid secretion creates an epithelium-intrinsic response unit that effects a physiological change within seconds of activation. This response mechanism is shared by tuft cells across tissues, and serves to regulate the epithelial secretion that is both a hallmark of Type 2 immunity and an essential component of homeostatic maintenance at mucosal barriers.

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From High-Throughput Screening to Target Validation: Benzo[d]isothiazoles as Potent and Selective Agonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 5 Possessing In Vivo Gastrointestinal Prokinetic Activity in Rodents

Cited by 10 publications

References 43 publications

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Identification of positive modulators of TRPM5 channel from a high-throughput screen using a fluorescent membrane potential assay

Tuft cell-derived acetylcholine regulates epithelial fluid secretion

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