Synthesis and characterization of novel isoform-selective IP6K1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2019-10, Vol.29 (19), p.126628-126628, Article 126628
• Main Authors: Wormald, Michael M., Ernst, Glen, Wei, Huijun, Barrow, James C.
• Format: Article
• Language: English
• Subjects: Inositol hexakisphosphate kinase; Inositol pyrophosphate; Kinases; Selective enzyme inhibitors; Structure activity relationships
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.126628

[Display omitted] •Structure-activity relationships based on a non-selective lead revealed compound 24 as a selective inhibitor of IP6K1.•Compound 24 has good selectivity over closely related kinases IP6K2 and IP6K3 as well as a panel of other diverse kinases.•Compound 24 is a useful tool to investigate the role of IP6K1 selective inhibitors. Inositol hexakisphosphate kinases (IP6Ks) have been increasingly studied as therapeutically interesting enzymes. IP6K isoform specific knock-outs have been used to successfully explore inositol pyrophosphate physiology and related pathologies. A pan-IP6K inhibitor, N2-(m-trifluorobenzyl)-N6-(p-nitrobenzyl) purine (TNP), has been used to confirm phenotypes observed in genetic knock-out experiments; however, it suffers by having modest potency and poor solubility making it difficult to handle for in vitro applications in the absence of DMSO. Moreover, TNP’s pan-IP6K inhibitory profile does not inform which IP6K isoform is responsible for which phenotypes. In this report we describe a series of purine-based isoform specific IP6K1 inhibitors. The lead compound was identified after multiple rounds of SAR and has been found to selectively inhibit IP6K1 over IP6K2 or IP6K3 using biochemical and biophysical approaches. It also boasts increased solubility and IP6K1 potency over TNP. These new compounds are useful tools for additional assay development and exploration of IP6K1 specific biology.