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
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
iScience. 2021 Nov 14;24(12):103442. doi: 10.1016/j.isci.2021.103442. eCollection 2021 Dec 17.
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 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 organoids and serial tumor transplantation.
癌症干细胞（CSCs）在肿瘤发生和治疗抗性中起着关键作用，这一点已有文献记载。尽管临床肿瘤学取得了重大进展，但癌症干细胞库仍然难以捉摸且难以消除。反向转折肽模拟物被表征为CBP/β-连环蛋白相互作用的破坏剂，是抑制癌症干细胞中过度活跃的经典Wnt/β-连环蛋白信号传导的一个有前景的途径。最近的研究表明，Sam68是癌症干细胞群体中反向转折肽模拟物反应的关键介质。我们使用计算和生化方法证实Sam68是反向转折肽模拟物的主要靶点。此外，我们执行了一个药物发现流程，以识别在转化的多能和结肠癌细胞模型中显示出卓越抗癌症干细胞活性的尚未表征的反向转折肽模拟物结构。因此，我们确定YB-0158是一种具有增强转化潜力的反向转折肽模拟小分子，可改变患者来源的类器官和连续肿瘤移植中人类结肠癌症干细胞的关键特征。
