Discovery of Natural Product ITPK1 Inhibitors using a Luciferase-Based High-Throughput Screen

Abstract ID 103203 Poster Board 489 Inositol phosphates (IPs) are regulatory molecules important in many cellular functions. Inositol-1,3,4,5,6-pentaphosphate (Ins(1,3,4,5,6)P₅) and inositol hexaphosphate (IP₆) interact with biological processes that are highly dysregulated in cancers, including telomere maintenance, DNA repair, transcription regulation, necroptosis, apoptosis resistance, and chromatin structure regulation. Inositol 3,4,5,6-tetraphosphate (Ins(3,4,5,6)P₄) modulates calcium-activated chloride ion channels, which is important in mitigating cystic fibrosis symptoms. IP6 has also been shown to be a co-factor for HIV-1 capsid formation. Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(3,4,5,6)P₄ to produce Ins(1,3,4,5,6)P₅, the precursor of IP₆. Therefore, ITPK1 can regulate the cellular flex of IP₆ and is thus an attractive target for cancer therapies and other diseases. We used a luciferase-based high-throughput screen to assess pre-fractionated natural product extracts. Following assay-guided fractionation of active pre-fractionated extracts, we discovered small molecules from natural products that inhibit ITPK1. Rational drug design will be employed to enhance potency in biochemical, cellular, and animal model assays.