7Q6T

Crystal structure of the bromodomain of ATAD2 with AZ13824374

Summary for 7Q6T

• Entry DOI: 10.2210/pdb7q6t/pdb
• Descriptor: ATPase family AAA domain-containing protein 2, SULFATE ION, (1R,9S,12R)-13-[[8-[[1-(2-fluoranyl-2-methyl-propyl)piperidin-4-yl]amino]-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]carbonyl]-12-propan-2-yl-11,13-diazatricyclo[7.3.1.0^{2,7}]trideca-2,4,6-trien-10-one, ... (4 entities in total)
• Functional Keywords: bromodomain, epigenetics, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16208.32

Authors

Patel, S.J.,Winter-Holt, J.J. (deposition date: 2021-11-09, release date: 2022-01-19, Last modification date: 2024-05-01)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.05 Å)