Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ

Michelle S Miller; Simon J Mountford; Jo-Anne Pinson; Zhaohua Zheng; Marco Künzli; Vanit Patel; Simon J Hogg; Jake Shortt; Ian G Jennings; Philip E Thompson

doi:10.1016/j.bmcl.2016.08.028

Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ

Bioorg Med Chem Lett. 2016 Oct 1;26(19):4790-4794. doi: 10.1016/j.bmcl.2016.08.028. Epub 2016 Aug 11.

Affiliations

¹ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
² Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
³ Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.

PMID: 27561716
DOI: 10.1016/j.bmcl.2016.08.028

Abstract

A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of 'on-target' activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.

Keywords: Isoform selectivity; Leukemia; Lymphoma; PI3 kinase inhibitor.

MeSH terms

Cell Line, Tumor
Enzyme Inhibitors / pharmacology*
Humans
Isoenzymes / antagonists & inhibitors*
Isoenzymes / chemistry
Phosphatidylinositol 3-Kinases / chemistry
Phosphoinositide-3 Kinase Inhibitors*

Substances

Enzyme Inhibitors
Isoenzymes
Phosphoinositide-3 Kinase Inhibitors