Abstract 7273: Small molecule activation of PP2A in the treatment of melanoma

Abstract

Abstract Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme functioning as a serine/threonine phosphatase, where it accounts for about 50-70% of all serine/threonine phosphorylation in the cell. Yet, PP2A is commonly inactivated in cancer, likely due to its role as a tumor suppressor. Due to the important role PP2A plays in many cellular processes, including those involved with tumor progression, there is a current need for novel therapeutics capable of targeting PP2A in cancer. Currently, none of the current PP2A modulators have made it into approved clinical use. As such, we have recently synthesized the PP2A activators, PPA24 and PPA27, using molecular docking and fragment-based drug design based on the structures of recently reported PP2A activators, iHAP1 and NSC49L. We were previously able to establish PPA24 as the lead compound in treating colorectal cancer (CRC) in vitro, compared to PPA27 and the parent compounds. Nevertheless, a single dose NCI-60 screen of both PPA24 and PPA27 indicated the cell selectivity present in both compounds and revealed the potential effect these compounds could have in other cancers. Further evaluation with an extended NCI-60 5-dose screen of PPA24 and PPA27 demonstrated a strong potential for both compounds in treating melanoma. Overall, the NCI-60 screen displayed PPA27 as most effective in melanoma across all cell lines screened, while PPA24 was found to be effective in both CRC and melanoma cell lines, agreeing with our previous findings. A cell viability screening of PPA24 and PPA27 in our laboratory across 5 melanoma cell lines (SK-MEL-2, SK-MEL-28, A375, Mel1241, and 451Lu) identified IC50 values in the range of 3.45-8.94 µM for PPA27 and 5.99-14.45 µM for PPA24. The parent compounds, iHAP1 and NSC49L, were also evaluated and NSC49L was found to be less effective in melanoma than previously found in CRC cells. Both PPA24 and PPA27 were found to be effective in cell lines with and without BRAFV600E mutation, though it appears the metastatic cell line, 451Lu, required an increased concentration for all compounds as compared to the IC50 values found in the other melanoma cell lines. Further evaluation revealed PPA24 and PPA27 as dose-dependently inducing apoptosis in cells with BRAFV600E (A375) and BRAF WT (SK-MEL-2). Together, these findings show the potential of PPA24 and PPA27 as therapeutic treatments for melanoma with or without BRAF mutations and are currently being further evaluated in several in vitro and in vivo melanoma models in our laboratory. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Satya Narayan, Arun K. Sharma. Small molecule activation of PP2A in the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7273.