7Q6W

Crystal structure of the bromodomain of ATAD2 with triazolopyridazine (cpd 22)

7Q6W の概要

• エントリーDOI: 10.2210/pdb7q6w/pdb
• 分子名称: ATPase family AAA domain-containing protein 2, SULFATE ION, (1R,9S)-13-[[3-methyl-8-[(1-methylpiperidin-4-yl)amino]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]carbonyl]-11,13-diazatricyclo[7.3.1.0^{2,7}]trideca-2,4,6-trien-10-one, ... (4 entities in total)
• 機能のキーワード: bromodomain, epigenetics, gene regulation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16202.23

構造登録者

Patel, S.J.,Winter-Holt, J.J. (登録日: 2021-11-09, 公開日: 2022-01-19, 最終更新日: 2024-05-01)

主引用文献

Winter-Holt, J.J.,Bardelle, C.,Chiarparin, E.,Dale, I.L.,Davey, P.R.J.,Davies, N.L.,Denz, C.,Fillery, S.M.,Guerot, C.M.,Han, F.,Hughes, S.J.,Kulkarni, M.,Liu, Z.,Milbradt, A.,Moss, T.A.,Niu, H.,Patel, J.,Rabow, A.A.,Schimpl, M.,Shi, J.,Sun, D.,Yang, D.,Guichard, S.
Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models.
J.Med.Chem., 65:3306-3331, 2022

PubMed Abstract: 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 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.

PubMed: 35133824
DOI: 10.1021/acs.jmedchem.1c01871

実験手法

X-RAY DIFFRACTION (1.96 Å)