Waitman Karoline, Parise-Filho Roberto
Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Future Med Chem. 2022 May;14(10):745-766. doi: 10.4155/fmc-2021-0276. Epub 2022 May 11.
Cancer is the second most common cause of death worldwide. It can easily acquire resistance to treatments, demanding new therapeutic strategies, such as simultaneous inhibition of kinase and HDAC enzymes with hybrid inhibitors. Different approaches to this have varied according to their targets, with a few common trends, such as the usage of heterocycle scaffolds for kinase interaction, especially pyrimidine and quinazolines, and hydroxamic acids and benzamides for HDAC inhibition. Besides the hybrid compounds developed focusing on the inhibition tyrosine kinase and receptor tyrosine kinase, many advances have occurred in the development of serine-threonine kinase/HDAC and lipid kinase/HDAC novel compounds. Here, the latest strategies employed in this research area will be reviewed, alongside trends in inhibitor design, and observed gaps will be punctuated.
癌症是全球第二大常见死因。它很容易对治疗产生耐药性,这就需要新的治疗策略,比如用杂交抑制剂同时抑制激酶和组蛋白去乙酰化酶(HDAC)。针对此的不同方法因其靶点而异,有一些共同趋势,比如使用杂环支架与激酶相互作用,尤其是嘧啶和喹唑啉,以及使用异羟肟酸和苯甲酰胺抑制HDAC。除了开发专注于抑制酪氨酸激酶和受体酪氨酸激酶的杂交化合物外,丝氨酸-苏氨酸激酶/HDAC和脂质激酶/HDAC新型化合物的开发也取得了许多进展。在此,将对该研究领域采用的最新策略进行综述,同时介绍抑制剂设计的趋势,并指出观察到的差距。