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12 results on '"Valentino, Stephen A."'

2. Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In VivoTarget Engagement

Author

Frey, Robin R., Jana, Navendu, Gorman, Jacob V., Wang, Jin, Smith, Heath A., Bromberg, Kenneth D., Thakur, Ashish, Doktor, Stella Z., Indulkar, Anura S., Jakob, Clarissa G., Upadhyay, Anup K., Qiu, Wei, Manaves, Vlasios, Gambino, Frank, Valentino, Stephen A., Montgomery, Debra, Zhou, Yebin, Li, Tao, Buchanan, Fritz G., Ferguson, Debra C., Kurnick, Matthew D., Kapecki, Nicolas, Lai, Albert, Michaelides, Michael R., and Penning, Thomas D.

Abstract

Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of in vivotarget engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing an azetidine-benzoxazole substituent. Compound 31potently engages the target in vivoand demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.

Published
2024
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4. The antioxidant-independent actions of vitamin E on gene expression

Author

Chen, Matthew, primary, Valentino, Stephen, additional, Ghelfi, Michael, additional, Poon, Jai-Fei, additional, Tariq, Hamza, additional, Zunica, Elizabeth, additional, Ulatowski, Lynn, additional, Chung, Stacey, additional, Cameron, Mark, additional, Cameron, Cheryl, additional, Atkinson, Jeffrey, additional, Pratt, Derek, additional, Finno, Carrie, additional, and Manor, Danny, additional

Published
2022
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6. Engineering Genetically Encoded Sensors to Study Purinergic Signaling

Author

Valentino, Stephen

Abstract

Extracellular adenosine triphosphate (ATP) is a key purinergic signal that mediates cell-to cell communication both within and between organ systems. We address the need for a robust and minimally invasive approach to measuring extracellular ATP by re-engineering the ATeam ATP sensor to be expressed on the cell surface. Using this approach, we image real-time changes in extracellular ATP levels with a sensor that is fully genetically-encoded and does not require an exogenous substrate. Using live-cell microscopy, we characterize sensor performance when expressed on cultured Neuro2A cells, and we measure both stimulated release of ATP and its clearance by ectonucleotidases. In addition, we increase the affinity of ATeam threefold by mutating the hinge region (R103A/R115A) of the epsilon subunit. Thus, this proof-of-principle demonstrates a sensor to report extracellular ATP dynamics that may be useful for studying purinergic signaling in living specimens.

Published
2018

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