Mukherjee Anirban, Suzuki Takayoshi
SANKEN, Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan.
J Med Chem. 2025 Jan 23;68(2):953-985. doi: 10.1021/acs.jmedchem.4c02474. Epub 2025 Jan 2.
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.
组蛋白甲基化是表观遗传学的一个关键方面，它与诸如G9a等特殊酶密切相关，G9a是一种组蛋白甲基转移酶（HMT），可催化组蛋白H3赖氨酸9（H3K9）和H3K27的甲基化。除了组蛋白修饰外，G9a还通过调节DNA甲基化模式来调控诸如脱氧核糖核酸（DNA）复制、损伤修复和基因表达等重要的细胞过程。G9a的失调和过表达与癌症的发生、发展和转移密切相关，使其成为抗癌治疗的一个有吸引力的靶点。此外，在阿尔茨海默病（AD）中发现了异常水平的H3K9二甲基化，这拓宽了表观遗传学在各种病理中的影响范围。对有效治疗方法的探索导致了众多G9a抑制剂/降解剂的发现，每种抑制剂/降解剂都显示出破坏异常信号通路的潜力。这一观点为G9a调节剂作为治疗一系列疾病的有前景候选药物的不断发展的潜力和进展提供了有价值的见解。
