Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856

被引：30

作者：

Perreault, Stephane ^{[1
]}

Chandrasekhar, Jayaraman ^{[1
]}

Cui, Zhi-Hua ^{[1
]}

Evarts, Jerry ^{[1
,3
]}

Hao, Jia ^{[2
]}

Kaplan, Joshua A. ^{[2
]}

Kashishian, Adam ^{[1
]}

Keegan, Kathleen S. ^{[1
]}

Kenney, Thomas ^{[1
]}

Koditek, David ^{[2
]}

Lad, Latesh ^{[2
]}

Lepist, Eve-Irene ^{[2
]}

McGrath, Mary E. ^{[2
]}

Patel, Leena ^{[1
]}

Phillips, Bart ^{[2
]}

Therrien, Joseph ^{[1
]}

Treiberg, Jennifer ^{[1
]}

Yahiaoui, Anella ^{[1
]}

Phillips, Gary ^{[1
]}

机构：

[1] Gilead Sci Inc, 199 E Blaine St, Seattle, WA 98102 USA

[2] Gilead Sci Inc, 333 Lakeside Dr, Foster City, CA 94404 USA

[3] Acerta Pharma, 15400 SE 30th Pl,Suite 206, Bellevue, WA 98007 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 04期

关键词：

SELECTIVE PI3K-BETA; BIOLOGICAL EVALUATION; RECEPTOR ANTAGONISTS; RATIONAL DESIGN; CANCER; PATHWAY; DERIVATIVES; IDELALISIB; SERIES; BIOISOSTERES;

D O I：

10.1021/acs.jmedchem.6b01821

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Phosphoinositide 3-kinase (PI3K) beta signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3K beta/delta inhibitors in which PI3K beta potency was built in a PI3K delta-selective template. This work led to the discovery of a highly selective PI3K beta/delta inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

引用

页码：1555 / 1567

页数：13

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