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Identification of ARUK2002821 as an isoform-selective PI5P4Kα inhibitor.

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Willems, Henriëtte MG  ORCID logo  https://orcid.org/0000-0001-7196-5975
Edwards, Simon 

Abstract

The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders. Many of the PI5P4Kα inhibitors that have been reported to date have suffered from poor selectivity and/or potency and the availability of better tool molecules would facilitate biological exploration. Herein we report a novel PI5P4Kα inhibitor chemotype that was identified through virtual screening. The series was optimised to deliver ARUK2002821 (36), a potent PI5P4Kα inhibitor (pIC50 = 8.0) which is selective vs. other PI5P4K isoforms and has broad selectivity against lipid and protein kinases. ADMET and target engagement data are provided for this tool molecule and others in the series, as well as an X-ray structure of 36 solved in complex with its PI5P4Kα target.

Description

Funder: Alborada Trust

Keywords

3404 Medicinal and Biomolecular Chemistry, 34 Chemical Sciences, 5.1 Pharmaceuticals, 5 Development of treatments and therapeutic interventions, Cancer

Journal Title

RSC Med Chem

Conference Name

Journal ISSN

2632-8682
2632-8682

Volume Title

14

Publisher

Royal Society of Chemistry (RSC)
Sponsorship
Alzheimer's Research UK (ARUK-2015DDI-CAM)
Alzheimer’s Research UK (grant: ARUK-2015DDI-CAM), with support from the ALBORADA Trust. The ALBORADA Drug Discovery Institute is core funded by Alzheimer’s Research UK (registered charity No. 1077089 and SC042474)