SMARCA2 protein: Structure, function and perspectives of drug design

Abstract

SMARCA2 is an ATPase that regulates chromatin structure via ATP pathways, controlling cell division and differentiation. SMARCA2's bromodomain and ATPase domain, crucial for chromatin remodeling and cell regulation, are therapeutic targets in cancer treatment. This review explores the role of SMARCA2 in cancer development by studying its protein structure and physiological functions. It further discusses the roles and distinctions of SMARCA2 and its related family proteins in cancer. Additionally, this article categorizes known SMARCA2 inhibitors into four classes based on their basic structure and examines their structure-activity relationships (SAR). This review outlines the structural mechanisms of SMARCA2 inhibitors, highlighting interactions with specific amino acids. By analyzing the SAR of inhibitors, we propose a tailored inhibitor model for the bromodomain of SMARCA2, emphasizing α, γ-H-bond donors/acceptors, and β-rigid structures as crucial for effective binding. This research provides guidance for the design and optimization of future drugs targeting the SMARCA2 protein.