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Biology subjects

Paruchuri, S.

Publications and source records attributed to Paruchuri, S..

3 recordsLinked to original sources
bioRxiv2025

TRPV4 Channels Mediate Bladder Cancer Cell Proliferation, Migration and Chemoresistance

Bladder cancer (BLCA) is the second most common urologic cancer in the US and worldwide which mostly affects the aging population. Despite several ongoing clinical trials, treatment paradigms for BLCA have not changed significantly. Here, we investigated the expression of transient receptor potential vanilloid type 4 (TRPV4) in BLCA patients and its role in calcium influx, cell proliferation, and migration using normal human urothelial cells and BLCA cells. Bioinformatic analysis of the UALCAN and cBioPortal databases revealed that TRPV4 expression is significantly higher in human BLCA tissues compared to adjacent normal tissues. Further, the TRPV4 expression was markedly elevated in early-stage BLCA and upregulated in muscle-invasive bladder cancer (MIBC) tissues. TRPV4 is expressed in both normal urothelial (SV-HUC-1) and BLCA (T-24) cells and functional assays demonstrated enhanced TRPV4-mediated calcium influx in T-24 compared to SV-HUC-1 cells. T-24 cells exhibited higher spreading on extracellular matrix (ECM) gels with increasing stiffness (0.2, 8, and 50 kPa) and exhibited migratory phenotype compared to SV-HUC-1 cells. Pharmacological inhibition of TRPV4 significantly reduced proliferation and migration in T-24 cells but had minimal effects on normal cells. Finally, treatment with cisplatin significantly reduced TRPV4 protein levels and TRPV4-mediated calcium influx in chemosensitive UM-UC-3 cells, which remained unchanged in chemoresistant T-24 cells, suggesting a potential role of TRPV4 in chemoresistance. In conclusion, TRPV4 may contribute to bladder cancer progression by regulating cell proliferation and migration and may impart resistance to chemotherapy. Targeting TRPV4 could present a novel therapeutic approach for managing bladder cancer progression and overcoming chemoresistance. Significance StatementThis study identifies TRPV4 as a critical driver of BLCA progression. Elevated TRPV4 gene expression in both early-stage and muscle-invasive bladder cancer (MIBC) tissues is associated with increased calcium signaling, cell proliferation, and migration. Importantly, TRPV4 inhibition selectively reduces BLCA growth and motility. Furthermore, TRPV4 is downregulated by cisplatin in chemo-sensitive but not chemo-resistant BLCA cells, underscoring its key role in bladder cancer chemoresistance. These findings position TRPV4 as a therapeutic target for enhancing BLCA treatment and overcoming drug resistance.

cancer biology↗
bioRxiv2025

Identification of Antituberculars with Favorable Potency and Pharmacokinetics through Structure-Based and Ligand-Based Modeling

Drug discovery is inherently challenged by a multiple criteria decision making problem. The arduous path from hit discovery through lead optimization and preclinical candidate selection necessitates the evolution of a plethora of molecular properties. In this study, we focus on the hit discovery phase while beginning to address multiple criteria critical to the development of novel therapeutics to treat Mycobacterium tuberculosis infection. We develop a hybrid structure- and ligand-based pipeline for nominating diverse inhibitors targeting the {beta}-ketoacyl synthase KasA by employing a Bayesian optimization-guided docking method and an ensemble model for compound nominations based on machine learning models for in vitro antibacterial efficacy, as characterized by minimum inhibitory concentration (MIC), and mouse pharmacokinetic (PK) plasma exposure. The application of our pipeline to the Enamine HTS library of 2.1M molecules resulted in the selection of 93 compounds, the experimental validation of which revealed exceptional PK (41%) and MIC (19%) success rates. Twelve compounds meet hit-like criteria in terms of MIC and PK profile and represent promising seeds for future drug discovery programs.

microbiology↗
bioRxiv2023

Analytical Comparability to Evaluate Impact of Manufacturing Changes of ARX788, an Anti-HER2 ADC in Late-Stage Clinical Development

ARX788 is an anti-HER2 antibody drug conjugate (ADC) developed using Ambrx proprietary Engineered Precision Biologics technology. The manufacturing process of ARX788 has been optimized during the course of early to late-phase clinical development. A comprehensive evaluation of side-by-side comparability between pre- and post-change process for ARX788 drug substance and drug product from a quality perspective was conducted based on ICH Q5E guidelines consisting of batch release assays, physicochemical and biophysical characterization, biological characterization, and forced degradation studies. All results have demonstrated a high degree of similarity between the pre- and post-change ARX788 drug substance batches and drug product lots, demonstrating that the process manufacturing changes did not impact product quality.

cancer biology↗