Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

Blay, Vincent; Li, Mu Chun; Ho, Sunita P.; Stoller, Mashall L.; Hsieh, Hsing Pang; Houston, Douglas R.

doi:10.1016/j.apsb.2019.09.008

Cited by 12 publications

(5 citation statements)

References 54 publications

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“…As shown in supplementary Figure S3 , the IC50 of venetoclax was 0.48 μM. This value was higher for hepsin than for the one recently reported for indole derivatives [33]. The toxicity of these compounds has yet to be tested in humans, while the calculated IC50 of venetoclax for hepsin is within the concentration range tested in chronic lymphocytic leukemia cells [34].…”

Section: Resultsmentioning

confidence: 89%

Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

Rodenas

Peñas-Martínez

Pardo-Sánchez

et al. 2022

Preprint

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Hepsin is a type II transmembrane serine protease whose expression has been linked to greater tumorigenicity and worse prognosis in different tumors such as prostate and gastric cancer. Recently, our group described hepsin expression in the primary biopsy as a potential biomarker of thrombosis and metastasis in localized colorectal cancer patients. Here we explored the role of hepsin in this tumor. Hepsin overexpression increased Caco-2 cell migration and invasion, higher phosphorylation of Erk1/2 and STAT3 and led to more thrombin generation in plasma. Indeed, our study revealed higher plasma levels of hepsin in metastatic colorectal cancer, which was associated with a greater tendency toward thrombosis. By virtual screening of a FDA-approved drug library, we identified venetoclax as a potent hepsin inhibitor, reducing the metastatic and prothrombotic phenotype of Caco-2 cells, but not of other colorectal cancer cells without hepsin expression. Interestingly, pre-treating Caco-2 cells overexpressing hepsin with venetoclax reduced its in vivo invasiveness. Taken together, our results demonstrate that elevated hepsin levels correlate with a more aggressive and prothrombotic tumor phenotype. Likewise, they evidence an antitumor role for venetoclax as a hepsin inhibitor. This lays the groundwork for molecular targeted therapy for colorectal cancer.

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Section: Resultsmentioning

confidence: 89%

Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

Rodenas

Peñas-Martínez

Pardo-Sánchez

et al. 2022

Preprint

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“…We used AutoDock Vina [29] to perform molecular docking between selected ligands and the EGFR and VEGFR-2 receptor proteins. AutoDock Vina employs an amalgam of scienti c and knowledgebased scoring systems that were developed using nonlinear regression on an extensive dataset (PDBbind) [44] . The software was created at the Scripps Research Institute [45] and can be accessed by anyone on the Internet.…”

Section: Molecular Docking Analysismentioning

confidence: 99%

Identification of dual inhibitors for EGFR(T790M/C797S) and VEGFR-2 in Non-Small Cell Lung Cancer from Moringa oleifera derived phytochemicals: An In-silico Approach

Munna,

Tusar,

Shanta

et al. 2024

Preprint

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Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality on a global scale for both men and women. At present, the treatment of NSCLC involves the use of tyrosine kinase inhibitors (TKIs), which specifically target EGFR. However, resistance mechanisms like the emergence of T790M and C797S EGFR mutations and increased expression of VEGFR-2 often impede the efficacy of various generations of TKIs. Thus, EGFR and VEGFR-2 offer a great opportunity to treat NSCLC through the development of multi-targeted drugs. Our study aims to identify potential inhibitors by thoroughly evaluating the biological activity of M. oleifera-derived compounds that could serve as novel dual inhibitors of EGFR(T790M/C797S) and VEGFR-2, resulting in a synergistic inhibitory effect on these signaling pathways. We identified five potential phytocompounds from M. oleifera (hesperetin, gossypetin, quercetagetin, gallocatechin, and epigallocatechin) that showed significant binding affinity in virtual screening and multi-stage molecular docking analysis with remarkable drug-likeness and ADMET properties. These selected drug candidates also strongly bound and stayed stable with the receptors during the 200 ns MD simulation and MM-GBSA calculation. These findings indicate that these therapeutic candidates have the capacity to precisely target both EGFR and VEGFR-2 and can potentially act on both of these pathways as a single agent.

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“…Furthermore, numerous novel drugs are being developed based on the specific signatures detected by scRNA-seq. For example, several HPN -targeting inhibitors have been designed to enhance PCa treatment [ 145 , 146 ].…”

Section: Scrna-seq Analysis In Pca For Clinical Applicationsmentioning

confidence: 99%

The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy

Feng,

Zhu,

Wang

et al. 2024

Military Med Res

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In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Starting from the perspective of RNA sequencing technology, this review outlined the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.

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Design of drug-like hepsin inhibitors against prostate cancer and kidney stones

Cited by 12 publications

References 54 publications

Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

Pro-tumor and prothrombotic activities of hepsin in colorectal cancer cells and suppression by venetoclax

Identification of dual inhibitors for EGFR(T790M/C797S) and VEGFR-2 in Non-Small Cell Lung Cancer from Moringa oleifera derived phytochemicals: An In-silico Approach

The implications of single-cell RNA-seq analysis in prostate cancer: unraveling tumor heterogeneity, therapeutic implications and pathways towards personalized therapy

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