Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

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

doi:10.1016/j.isci.2021.103442

Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

iScience. 2021 Nov 14;24(12):103442. doi: 10.1016/j.isci.2021.103442. eCollection 2021 Dec 17.

Affiliation

¹ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.

Abstract

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.

Keywords: Biochemistry; Cancer; Pharmacology; Stem cells research.