Constellation Pharmaceuticals Inc., Cambridge, MA, USA.
Nat Chem Biol. 2022 Feb;18(2):124-133. doi: 10.1038/s41589-021-00920-5. Epub 2021 Dec 24.
More than a decade after the launch of DNA methyltransferase and histone deacetylase inhibitors for the treatment of cancer, 2020 heralded the approval of the first histone methyltransferase inhibitor, revitalizing the concept that targeted manipulation of the chromatin regulatory landscape can have profound therapeutic impact. Three chromatin regulatory pathways-DNA methylation, histone acetylation and methylation-are frequently implicated in human cancer but hundreds of potentially druggable mechanisms complicate identification of key targets for therapeutic intervention. In addition to human genetics and functional screening, chemical biology approaches have proven critical for the discovery of key nodes in these pathways and in an ever-increasing complexity of molecularly defined human cancer contexts. This review introduces small molecule targeting approaches, showcases chemical probes and drug candidates for epigenetic writer enzymes, illustrates molecular features that may represent epigenetic dependencies and suggests translational strategies to maximize their impact in cancer therapy.
在 DNA 甲基转移酶和组蛋白去乙酰化酶抑制剂用于癌症治疗启动十多年后，2020 年迎来了首个组蛋白甲基转移酶抑制剂的批准，这重新激发了一个概念，即靶向调控染色质调控景观可以产生深远的治疗效果。DNA 甲基化、组蛋白乙酰化和甲基化这三种染色质调控途径在人类癌症中经常被涉及，但数以百计的潜在可用药机制使得确定治疗干预的关键靶点变得复杂。除了人类遗传学和功能筛选外，化学生物学方法已被证明对这些途径中关键节点的发现以及在分子定义的人类癌症环境中日益增加的复杂性至关重要。这篇综述介绍了小分子靶向方法，展示了用于表观遗传写入酶的化学探针和药物候选物，说明了可能代表表观遗传依赖性的分子特征，并提出了转化策略，以最大限度地提高它们在癌症治疗中的影响。
