ATPase family AAA domain-containing protein 2 (ATAD2) has been recognized as a key oncogene that regulates chromatin remodeling, transcription, and cancer progression. As a member of the bromodomain (BRD) family, ATAD2 plays a crucial role in epigenetic modifications and is associated with multiple malignancies. Despite being considered an undruggable target in the past, crystallography and computational modeling have significantly accelerated ATAD2 drug discovery and development. This review provides a comprehensive overview of the structural features, functional roles, and biological significance of ATAD2, particularly in the context of cancer. We present an in-depth overview of different molecular strategies reported in the literature to suppress ATAD2 expression, including genetic and pharmacological approaches, and discuss their mechanistic and therapeutic implications. Particular emphasis is given to recent efforts in developing small-molecule inhibitors, detailing their binding interactions, therapeutic potential, and challenges in clinical translation. In addition, we performed alanine scanning calculations on molecular dynamics (MD)-simulated trajectories derived from protein–ligand complexes based on X-ray co-crystal structures containing three distinct ligands with different binding modes. This analysis provided critical insights into the binding interface of BRD-ATAD2, enhancing our understanding of its ligand interactions. Furthermore, we examine the emerging roles of ATAD2 in mediating resistance to cancer therapies, underscoring its potential as a target for overcoming drug resistance. By integrating structural insights, mechanistic studies, drug discovery efforts, and the challenges of developing ATAD2-targeted cancer therapies, this review emphasizes the need for further research to optimize ATAD2 inhibition strategies and explore its full therapeutic potential in oncology.
ATP酶家族AAA结构域蛋白2（ATAD2）已被确认为调控染色质重塑、转录及癌症进展的关键癌基因。作为溴结构域（BRD）家族成员，ATAD2在表观遗传修饰中发挥关键作用，并与多种恶性肿瘤密切相关。尽管过去曾被视为不可成药靶点，晶体学与计算建模技术的进步显著加速了ATAD2药物的研发进程。本综述系统阐述了ATAD2的结构特征、功能作用及其在癌症中的生物学意义，深入梳理了文献报道中抑制ATAD2表达的不同分子策略（包括遗传学与药理学方法），并探讨其作用机制与治疗意义。文章重点评述了近年来小分子抑制剂研发的最新进展，详细解析其结合模式、治疗潜力及临床转化挑战。此外，我们基于包含三种不同结合模式配体的X射线共晶结构，对蛋白质-配体复合物进行分子动力学模拟轨迹的丙氨酸扫描计算，该分析为BRD-ATAD2结合界面提供了关键见解，深化了对其配体相互作用机制的理解。同时，我们探讨了ATAD2在介导癌症治疗耐药性中的新兴作用，凸显其作为克服耐药性靶点的潜力。通过整合结构解析、机制研究、药物发现成果及ATAD2靶向癌症疗法开发面临的挑战，本综述强调需要进一步优化ATAD2抑制策略，并充分挖掘其在肿瘤治疗领域的应用潜力。
ATAD2 as a Cancer Target: Insights into Its Structure, Functions, Mechanisms, and Drug Development
肿瘤(癌症)患者之家