Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models

被引：20

作者：

Winter-Holt, Jon J. ^{[2
]}

Bardelle, Catherine ^{[1
]}

Chiarparin, Elisabetta ^{[2
]}

Dale, Ian L. ^{[3
]}

Davey, Paul R. J. ^{[2
]}

Davies, Nichola L. ^{[2
]}

Denz, Christopher ^{[4
]}

Fillery, Shaun M. ^{[2
]}

Guerot, Carine M. ^{[2
]}

Han, Fujin ^{[5
]}

Hughes, Samantha J. ^{[2
]}

Kulkarni, Meghana ^{[4
,6
]}

Liu, Zhaoqun ^{[5
]}

Milbradt, Alexander ^{[3
]}

Moss, Thomas A. ^{[2
]}

Niu, Huijun ^{[5
]}

Patel, Joe ^{[3
,7
]}

Rabow, Alfred A. ^{[2
,8
]}

Schimpl, Marianne ^{[3
]}

Shi, Junjie ^{[5
]}

Sun, Dongqing ^{[5
]}

Yang, Dejian ^{[5
]}

Guichard, Sylvie ^{[4
,9
]}

机构：

[1] AstraZeneca, BioPharmaceut R&D, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Oncol, Cambridge CB4 0FZ, England

[3] AstraZeneca, BioPharmaceut R&D, Cambridge CB4 0FZ, England

[4] AstraZeneca, Oncol R&D, Waltham, MA 02451 USA

[5] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

[6] BAKX Therapeut, 551 Mt Guardian Rd Ext,POB 398, Bearsville, NY 12409 USA

[7] Treeline Biosci, 500 Arsenal St, Watertown, MA 02472 USA

[8] 20 Bridge St, Macclesfield SK11 6EG, Cheshire, England

[9] Forma Therapeut, 300 North Beacon St,Suite 501, Watertown, MA 02472 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 04期

关键词：

CHEMICAL PROBE; FAMILY; SCALE;

D O I：

10.1021/acs.jmedchem.1c01871

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.

引用

页码：3306 / 3331

页数：26

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