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

  • J Med Chem. 2024 Jul 14. doi: 10.1021/acs.jmedchem.4c01077.
Hannah Johnson  1 ,  Amandeep Singh  1 ,  Asif Raza  1 ,  Congzhou M Sha  1 ,  Jian Wang  1 ,  Krishne Gowda  1 ,  Zhihang Shen  2 ,  Haritha Nair  3 ,  Chenglong Li  2 ,  Nikolay V Dokholyan  1 ,  Satya Narayan  3 ,  Arun K Sharma  1
Affiliations
  • 1. Department of Pharmacology, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, United States.
  • 2. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States.
  • 3. Department of Anatomy and Cell Biology, College of Medicine, University of Florida, 1200 Newell Drive, Gainesville, Florida 32610, United States.
PMID: 39004939 DOI: 10.1021/acs.jmedchem.4c01077
Abstract

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.

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