G9a/GLP Modulators: Inhibitors to Degraders

Abstract

Histone methylation, a crucial aspect of epigenetics, intricately involves specialized enzymes such as G9a, a histone methyltransferase (HMT) catalyzing the methylation of histone H3 lysine 9 (H3K9) and H3K27. Apart from histone modification, G9a regulates essential cellular processes such as deoxyribonucleic acid (DNA) replication, damage repair, and gene expression via modulating DNA methylation patterns. The dysregulation and overexpression of G9a are intricately linked to cancer initiation, progression, and metastasis, making it a compelling target for anticancer therapy. Moreover, aberrant levels of H3K9 dimethylation were identified in Alzheimer's disease (AD), broadening the scope of epigenetic implications across various pathologies. The quest for potent therapy has resulted in the identification of numerous G9a inhibitors/degraders, each demonstrating the potential to disrupt aberrant signaling pathways. This perspective provides valuable insights into the evolving potential and advancement of G9a modulators as promising candidates for treating a spectrum of diseases.