Coluccia Antonio, La Regina Giuseppe, Naccarato Valentina, Nalli Marianna, Orlando Viviana, Biagioni Stefano, De Angelis Maria Laura, Baiocchi Marta, Gautier Candice, Gianni Stefano, Di Pastena Fiorella, Di Magno Laura, Canettieri Gianluca, Coluccia Addolorata Maria Luce, Silvestri Romano
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
ACS Med Chem Lett. 2019 Jan 14;10(4):499-503. doi: 10.1021/acsmedchemlett.8b00532. eCollection 2019 Apr 11.
Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents.
旨在调节NHERF1活性而非其整体表达的靶向方法，将更有利于保留这种多功能蛋白的正常功能。我们将注意力集中在通过瞬时磷酸化开关控制其膜募集/位移的NHERF1/PDZ1结构域上。我们在此报告新型NHERF1 PDZ1结构域抑制剂的设计与合成。当这些化合物与β-连环蛋白拮抗剂联合使用时，对目前可用的Wnt/β-连环蛋白靶向药物难治的结肠癌细胞的凋亡死亡具有潜在治疗价值。
