7q6u
From Proteopedia
Crystal structure of the bromodomain of ATAD2 with phenol HTS hit (cpd 6)
Structural highlights
Function[ATAD2_HUMAN] May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.[1] Publication Abstract from PubMedATAD2 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. Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models.,Winter-Holt JJ, Bardelle C, Chiarparin E, Dale IL, Davey PRJ, Davies NL, Denz C, Fillery SM, Guerot CM, Han F, Hughes SJ, Kulkarni M, Liu Z, Milbradt A, Moss TA, Niu H, Patel J, Rabow AA, Schimpl M, Shi J, Sun D, Yang D, Guichard S J Med Chem. 2022 Feb 8. doi: 10.1021/acs.jmedchem.1c01871. PMID:35133824[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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