ATAD2 as a Cancer Target: Insights into Its Structure, Functions, Mechanisms, and Drug Development

TL;DR

This review explores ATAD2, a protein linked to cancer progression, and discusses its structure, functions, and potential as a target for new cancer therapies.

Contribution

The paper provides new insights into ATAD2's role in cancer and evaluates recent drug development strategies, including computational and small-molecule approaches.

Findings

Elevated ATAD2 levels promote tumor growth, survival, and resistance to therapies.

Recent computational and structural studies have enhanced understanding of ATAD2's interactions and drug binding.

Small-molecule inhibitors are being developed to target ATAD2, with challenges in clinical translation identified.

Abstract

Cancer remains a major cause of death worldwide, driven by numerous molecular pathways that support tumor growth, survival, and progression. The search for new therapeutic targets has identified several promising proteins that act through distinct mechanisms. One such target is ATPase family AAA domain-containing protein 2 (ATAD2), a protein that regulates how genes are organized and expressed in cells. Elevated ATAD2 levels are found in many cancers, where it promotes tumor proliferation, survival, and metastasis, and emerging evidence suggests it may contribute to resistance against existing therapies. This review provides a comprehensive overview of ATAD2, including its structure, biological functions, and role in cancer progression. It also highlights strategies being explored to inhibit ATAD2, particularly small-molecule approaches, and presents computational insights that enhance our understanding of its interactions. By consolidating these findings, the review aims to guide future research toward effective ATAD2-targeted therapies.

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.

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