This proposed collaboration is between the Center for Integrative Chemical Biology and Drug Discovery (CICBDD) at the University of North Carolina, Chapel Hill, and Dr. Stephen Shears at NIEHS, Research Triangle Park. We propose to develop the methodology that can applied to a high throughput screen to identify lead chemical probes to inhibit a functionally-specialized pair of small molecule kinases known as IP7Ks (a.k.a. PPIP5Ks). These cell-signaling enzymes (IP7K1/PPIP5K1 and IP7K2/PPIP5K2), synthesize diphosphorylated inositol phosphates: the diphosphoinositol pentakisphosphate, 1-IP7, and bis-diphosphoinositol tetrakisphosphate, IP8. These reactions catalyzed by IP7Ks promote cell proliferation through activation of the protein kinase, AKT. Moreover, molecular pathways controlling pro-inflammatory interferon transcription are activated by IP7Ks during viral infection These same pathways activate interferon transcription in response to metabolic inflammation, such as that which characterizes diabetes and obesity. Thus, IP7Ks are potential pharmacological targets for new anti-cancer and anti- inflammatory therapies. The development of probes that alter the activities of IP7Ks also offers opportunities for researchers to identify and study additional functions of the IP7Ks. Thus, the focus of this application is to develop and validate assay methods applicable to high throughput screening, with accompanying orthogonal and in-cell assays, to screen chemical libraries with the aim of discovering novel, cell- permeant modifiers of IP7K activity.
The focus of this application is to develop high throughput screening and virtual screening assays to discover novel, cell-permeant modifiers of IP7K activity. There are two groups of enzymes that synthesize inositol pyrophosphates: IP6K1/2/3 and IP7K1/2. There is growing evidence that this family of molecules has several different cellular roles that are highly pertinent to the development and progression of metabolic diseases (diabetes, obesity), ageing, and cancer.
|Puhl-Rubio, Ana C; Stashko, Michael A; Wang, Huanchen et al. (2018) Use of Protein Kinase-Focused Compound Libraries for the Discovery of New Inositol Phosphate Kinase Inhibitors. SLAS Discov 23:982-988|
|Baughman, Brandi M; Wang, Huanchen; An, Yi et al. (2016) A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors. PLoS One 11:e0164378|