1. Academic Validation
  2. Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

Pharmacological targeting of Sam68 functions in colorectal cancer stem cells

  • iScience. 2021 Nov 14;24(12):103442. doi: 10.1016/j.isci.2021.103442.
Angelique N Masibag 1 Christopher J Bergin 1 Joshua R Haebe 1 Aïcha Zouggar 1 Muhammad S Shah 1 Tamara Sandouka 1 Amanda Mendes da Silva 1 François M Desrochers 1 Aube Fournier-Morin 1 Yannick D Benoit 1
Affiliations

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.

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