Department of Pharmacology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, United States.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States.
J Med Chem. 2024 Oct 24;67(20):18070-18089. doi: 10.1021/acs.jmedchem.4c01077. Epub 2024 Jul 14.
A series of compounds were designed utilizing molecular modeling and fragment-based design based upon the known protein phosphatase 2A (PP2A) activators, and , and evaluated for their ability to inhibit the viability of colorectal cancer (CRC) and folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX)-resistant CRC cells. () was identified as the most cytotoxic compound with IC values in the range of 2.36-6.75 μM in CRC and FOLFOX-resistant CRC cell lines. It stimulated PP2A activity to a greater extent, displayed lower binding energies through molecular docking, and showed higher binding affinity through surface plasmon resonance for PP2A catalytic subunit α than the known PP2A activators. dose-dependently induced apoptosis and oxidative stress, decreased the level of c-Myc expression, and synergistically potentiated cytotoxicity when combined with gemcitabine and cisplatin. Furthermore, a -encapsulated nanoformulation significantly inhibited the growth of CRC xenografts without systemic toxicities. Together, these results signify the potential of as a novel PP2A activator and a prospective therapeutic for CRC and FOLFOX-resistant CRC.
利用分子建模和基于片段的设计，设计了一系列化合物，这些化合物基于已知的蛋白磷酸酶 2A (PP2A) 激活剂和，评估它们抑制结直肠癌细胞（CRC）和叶酸、5-氟尿嘧啶和奥沙利铂（FOLFOX）耐药 CRC 细胞活力的能力。被鉴定为最具细胞毒性的化合物，在 CRC 和 FOLFOX 耐药 CRC 细胞系中的 IC 值范围为 2.36-6.75 μM。它更有效地刺激了 PP2A 活性，通过分子对接显示出更低的结合能，并且通过表面等离子体共振显示出对 PP2A 催化亚基 α 的更高结合亲和力，优于已知的 PP2A 激活剂。剂量依赖性地诱导细胞凋亡和氧化应激，降低 c-Myc 表达水平，并与吉西他滨和顺铂联合使用时协同增强细胞毒性。此外，封装在中的纳米制剂显著抑制了 CRC 异种移植物的生长，而没有全身毒性。总之，这些结果表明作为一种新型的 PP2A 激活剂，具有治疗 CRC 和 FOLFOX 耐药 CRC 的潜力。
