Fragment-Based Screening Identifies New Quinazolinone-Based Inositol Hexakisphosphate Kinase (IP6K) Inhibitors

Tyler Heitmann; Gangling Liao; Pablo de León; Glen Ernst; Ingrid Buchler; Huijun Wei; Evgeny Shlevkov; Dean Brown; Martina Fitzek; Matthew Collier; David M Smith; James C Barrow

doi:10.1021/acsmedchemlett.3c00409

Fragment-Based Screening Identifies New Quinazolinone-Based Inositol Hexakisphosphate Kinase (IP6K) Inhibitors

ACS Med Chem Lett. 2023 Nov 28;14(12):1760-1766. doi: 10.1021/acsmedchemlett.3c00409. eCollection 2023 Dec 14.

Authors

Tyler Heitmann¹, Gangling Liao¹, Pablo de León¹, Glen Ernst¹, Ingrid Buchler¹, Huijun Wei^{1

2}, Evgeny Shlevkov¹, Dean Brown³, Martina Fitzek⁴, Matthew Collier⁴, David M Smith⁵, James C Barrow^{1

2}

Affiliations

¹ Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
² Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
³ Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Boston, Massachusetts 02451, United States.
⁴ Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, U.K.
⁵ Emerging Innovations Unit, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.

PMID: 38116421
PMCID: PMC10726443 (available on 2024-12-14)
DOI: 10.1021/acsmedchemlett.3c00409

Abstract

A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.