Small molecule compounds targeting G9a/GLP: Recent advances and perspectives

Abstract

As an important member of the histone methyltransferase family, G9a/GLP has been shown to be closely related to the occurrence and development of various diseases, such as tumors, fibrosis, and malaria. Selective small molecule inhibitors of G9a/GLP were first reported in 2007, and over the decade since then, more than 40 different types of G9a modulators have been developed. Classification by binding site includes s-adenosylmethionine (SAM)-competitive inhibitors and substrate-competitive inhibitors. According to the mechanism of action, these compounds can be divided into reversible inhibitors, irreversible inhibitors, dual inhibitors, degraders, etc. In this paper, we systematically reviewed the discovery methods, design strategies, structural optimization processes, binding modes, biological activity data, and pharmacokinetic properties of small molecules targeting G9a/GLP. This paper analyzed the challenges and opportunities in the development of small molecule compounds targeting G9a/GLP, aiming to offer valuable insights and perspectives for pharmaceutical researchers.