Discovery of ITPK1 inhibitors Using a Luciferase-based High-Throughput Screen and X-Ray Crystallography

Authors

• MY Ng

Abstract

Inositol phosphates (IPs), a hexose with six hydroxyl groups that can be mono- or poly-phosphorylated, play crucial roles in various biological processes. Specifically, Ins(1,3,4,5,6)P5 (or IP5), and other higher-order IPs, like Ins(1,2,3,4,5,6)P6 (or IP6), have been demonstrated to associate with proteins involved in highly dysregulated processes in cancers like telomere and transcription regulation, DNA repair, apoptosis resistance, necroptosis, and chromatin structure organization. On the other hand, Inositol 3,4,5,6-tetraphosphate (Ins(3,4,5,6)P4) (or IP4), inhibits calcium-activated chloride ion channels, modulating the severity of cystic fibrosis symptoms. Inositol-tetrakisphosphate 1-kinase (ITPK1) transforms IP4 to IP5, the precursor to the critical Ins(1,2,3,4,5,6)P6, making ITPK1 a promising molecular target for cancer therapies. Furthermore, the capability to modulate ITPK1 activity enables the further elucidation of the significance of IPs in cell biology. There are no known ITPK1 inhibitors currently. To discover ITPK1 inhibitors, we have developed a luciferase-based high-throughput screen to assess libraries of synthetic compounds and natural products for ITPK1 modulators. Synthetic active compounds were shown to be ATP competitors. The compound with the highest affinity to ITPK1 was co-crystallized and shown to bind to the ATP binding site. We further demonstrated that this compound was able to modulate IP5 and IP6 levels in SW620 colorectal cancer cells.

Scientific Focus Area: Molecular Biology and Biochemistry

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