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

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.