Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

• 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
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103442

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;