Identification of a Novel Protein Phosphatase 2A Activator, PPA24, as a Potential Therapeutic for FOLFOX-Resistant Colorectal Cancer

• Published in: Journal of medicinal chemistry Vol. 67; no. 20; pp. 18070 - 18089
• Main Authors: Johnson, Hannah, Singh, Amandeep, Raza, Asif, Sha, Congzhou M., Wang, Jian, Gowda, Krishne, Shen, Zhihang, Nair, Haritha, Li, Chenglong, Dokholyan, Nikolay V., Narayan, Satya, Sharma, Arun K.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.10.2024
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Drug Resistance, Neoplasm - drug effects; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Humans; Leucovorin - pharmacology; Leucovorin - therapeutic use; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Organoplatinum Compounds - therapeutic use; Protein Phosphatase 2 - antagonists & inhibitors; Protein Phosphatase 2 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01077

A series of compounds were designed utilizing molecular modeling and fragment-based design based upon the known protein phosphatase 2A (PP2A) activators, NSC49L and iHAP1, and evaluated for their ability to inhibit the viability of colorectal cancer (CRC) and folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX)-resistant CRC cells. PPA24 (19a) was identified as the most cytotoxic compound with IC50 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. PPA24 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 PPA24-encapsulated nanoformulation significantly inhibited the growth of CRC xenografts without systemic toxicities. Together, these results signify the potential of PPA24 as a novel PP2A activator and a prospective therapeutic for CRC and FOLFOX-resistant CRC.