Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

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 interacti...

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Published in:iScience 2021-12, Vol.24 (12), p.103442-103442, Article 103442
Main Authors: Masibag, Angelique N., Bergin, Christopher J., Haebe, Joshua R., Zouggar, Aïcha, Shah, Muhammad S., Sandouka, Tamara, Mendes da Silva, Amanda, Desrochers, François M., Fournier-Morin, Aube, Benoit, Yannick D.
Format: Article
Language:English
Subjects:
Biochemistry
Cancer
Pharmacology
Stem cells research
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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. [Display omitted] •Sam68 is a direct protein target of reverse-turn peptidomimetic small molecules•YB-0158 is a peptidomimetic structure with high predicted affinity for Sam68•YB-0158 elicits a cancer-selective response impeding main cancer stem cell hallmarks•YB-0158 blocks cancer stem cell activity in tumor organoids and in vivo systems Pharmacology; Biochemistry; Stem cells research; Cancer;
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2021.103442