2. Academic Validation
  3. Fragment-Based Screening Identifies New Quinazolinone-Based Inositol Hexakisphosphate Kinase (IP6K) Inhibitors

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.
Tyler Heitmann 1,  Gangling Liao 1,  Pablo de León 1,  Glen Ernst 1,  Ingrid Buchler 1,  Huijun Wei 1 2,  Evgeny Shlevkov 1,  Dean Brown 3,  Martina Fitzek 4,  Matthew Collier 4,  David M Smith 5,  James C Barrow 1 2
Affiliations

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 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.

Figures
Products