Abstract 1655: Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 83; no. 7_Supplement; p. 1655
• Main Authors: Johnson, Hannah, Singh, Amandeep, Raza, Asif, Sha, Congzhou M., Dokholyan, Nikolay V., Narayan, Satya, Sharma, Arun K.
• Format: Journal Article
• Language: English
• Published: 04.04.2023
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-1655

Abstract Protein phosphatase 2A (PP2A) is a diverse serine/threonine phosphatase that accounts for 50-70% of all serine/threonine phosphorylation in the cell. Due to the inactivation of PP2A in cancer, many of the cellular processes that PP2A regulates are aimed towards tumor progression. As such, the therapeutic targeting of PP2A in cancer is becoming a popular research avenue in the development of new chemotherapeutics. Currently, there have been a few PP2A activators observed to inhibit tumor progression in vitro and in vivo; however, these compounds have shown to have poor bioavailability, such as NSC49L, or uncertainty towards their ability to activate PP2A, as is the case with iHAP1. These hindrances demonstrate a need for further optimization of these molecules in order to produce a PP2A activator capable of inhibiting cancer without these limitations. As such, we have designed a series of compounds utilizing molecular modeling and fragment-based drug design based upon the known PP2A activators, NSC49L and iHAP1. These compounds were assessed for their ability to inhibit colon cancer (CRC) cells and FOLFOX-resistant CRC cells, where PPA24 was identified as the lead compound. The dose-response curves identified IC50 values in the range of 2.36-6.75µM for PPA24 across four CRC cell lines (HCT116, HT29, DLD1, and SW480) and two FOLFOX-resistant CRC cell lines (FOLFOX-HCT116 and FOLFOX-HT29), displaying more cytotoxicity than both the parent compounds and the other compounds in the series. Molecular docking recognized lower binding energies occurring during the association of PP2A with PPA24 than with either NSC49L or iHAP1. When examining the in vitro effect of PPA24 on stimulating PP2A activation, it was found that PPA24 significantly induced PP2A activity 2-3-fold higher than NSC49L or iHAP1. Likewise, PPA24 was able to induce apoptosis dose-dependently in both CRC and FOLFOX-resistant CRC cells. As PP2A is known for regulating the cell cycle progression, further exploration revealed PPA24 able to induce cell cycle arrest at the G2/M phase. And PP2A, being known as a regulator for many cellular processes, can be activated to assist in the degradation and inactivation of many signaling proteins such as c-myc, GSK3β, and ERK, which was observed in CRC cells treated with PPA24. Together, these results signify the potential of PPA24 to act as a novel PP2A activator in the treatment of CRC and FOLFOX-resistant CRC. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M. Sha, Nikolay V. Dokholyan, Satya Narayan, Arun K. Sharma. Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1655.