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

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.ATAD2是一种含溴结构域（bromodomain）的表观遗传学靶点，在多种癌症中呈过表达状态，被认为是潜在的肿瘤学治疗靶点。尽管已有多篇文献报道了数种小分子抑制剂，但这些抑制剂的细胞活性均不尽如人意。本研究通过高通量筛选发现了一系列新型ATAD2抑制剂，确认了溴结构域区域为其作用位点，并通过优化研究提升了初始命中化合物的效价、选择性与通透性。最终得到化合物5（AZ13824374），这是一种强效高选择性ATAD2抑制剂，在多种乳腺癌模型中均展现出细胞靶点结合活性与抗增殖活性。