Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

Summary: Cancer stem cells (CSCs) are documented to play a key role in tumorigenesis and therapy resistance. Despite significant progress in clinical oncology, CSC reservoirs remain elusive and difficult to eliminate. Reverse-turn peptidomimetics were characterized as disruptors of CBP/beta-Catenin...

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Autores principales: Angelique N. Masibag, Christopher J. Bergin, Joshua R. Haebe, Aïcha Zouggar, Muhammad S. Shah, Tamara Sandouka, Amanda Mendes da Silva, François M. Desrochers, Aube Fournier-Morin, Yannick D. Benoit
Formato: article
Lenguaje:EN
Publicado: Elsevier 2021
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Acceso en línea:https://doaj.org/article/a4b364fa1b8740e1b8dceb3a7778dcb2
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Sumario:Summary: Cancer stem cells (CSCs) are documented to play a key role in tumorigenesis and therapy resistance. Despite significant progress in clinical oncology, CSC reservoirs remain elusive and difficult to eliminate. Reverse-turn peptidomimetics were characterized as disruptors of CBP/beta-Catenin interactions and represent a promising avenue to curb hyperactive canonical Wnt/beta-Catenin signaling in CSCs. Recent studies suggested Sam68 as a critical mediator of reverse-turn peptidomimetics response in CSC populations. Using computational and biochemical approaches we confirmed Sam68 as a primary target of reverse-turn peptidomimetics. Furthermore, we executed an in silico drug discovery pipeline to identify yet uncharacterized reverse-turn peptidomimetic structures displaying superior anti-CSC activity in transformed pluripotent and colorectal cancer cell models. Thus, we identified YB-0158 as a reverse-turn peptidomimetic small molecule with enhanced translational potential, altering key hallmarks of human colorectal CSCs in patient-derived ex vivo organoids and in vivo serial tumor transplantation.