Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Miller, Michelle S.; Mountford, Simon J.; Pinson, Jo-Anne; Zheng, Zhaohua; Künzli, Marco; Patel, Vanit; Hogg, Simon J.; Shortt, Jake; Jennings, Ian G.; Thompson, Philip E.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 19(2016)
• Page Start: 4790
• Page End: 4794
• Publication Date: 2016-10-01
• Subjects: PI3 kinase inhibitor -- Isoform selectivity -- Leukemia -- Lymphoma; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.