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

被引：9

作者：

Miller, Michelle S. ^{[1
,5
]}

Mountford, Simon J. ^{[1
]}

Pinson, Jo-Anne ^{[1
]}

Zheng, Zhaohua ^{[1
]}

Kunzli, Marco ^{[1
]}

Patel, Vanit ^{[1
]}

Hogg, Simon J. ^{[2
,3
]}

Shortt, Jake ^{[2
,3
,4
]}

Jennings, Ian G. ^{[1
]}

Thompson, Philip E. ^{[1
]}

机构：

[1] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic 3052, Australia

[2] Peter MacCallum Canc Ctr, Canc Therapeut Program, Melbourne, Vic 3002, Australia

[3] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3002, Australia

[4] Monash Univ, Sch Clin Sci, Monash Hlth, Clayton, Vic 3168, Australia

[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 19期

基金：

英国医学研究理事会;

关键词：

PI3 kinase inhibitor; Isoform selectivity; Leukemia; Lymphoma; ACUTE LYMPHOBLASTIC-LEUKEMIA; NONCONSERVED AMINO-ACIDS; B-CELL MALIGNANCIES; PHOSPHOINOSITIDE; 3-KINASE; PHOSPHATIDYLINOSITOL-3-KINASE INHIBITOR; PI3K; LYMPHOMA; MUTAGENESIS; NVP-BKM120; IDELALISIB;

D O I：

10.1016/j.bmcl.2016.08.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of PI3K delta 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 PI3K delta. As a marker of 'on-target' activity and permeability, a selection of the most potent PI3K delta inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4790 / 4794

页数：5

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