Medvet Science. 65 Hardys Rd, Underdale, Adelaide, 5032, Australia.
Incheon National University, Building 29, 119 Academy-ro, Yeonsu-gu, Incheon 22012, Korea.
Curr Pharm Des. 2017 Nov 16;23(29):4311-4320. doi: 10.2174/1381612823666170710144106.
Despite the breakthroughs that have been achieved, significant unmet needs relating to the inadequate efficacy and toxicity of currently-available cancer therapies remain. Kinase inhibitors are a class of agents that target signaling factors responsible for the survival of malignant cells, and may address at least some of these issues. The concept of synthetic lethality provides a potential solution to counteract pathway redundancies, and refers to situations in which a mutation in one of two particular genes alone permits cell survival, while simultaneous mutation in both results in cell death. When exploited in the context of cancer therapy, pathways that are uniquely upregulated in cancer cells become selective targets, with reduced off-target toxicity toward their healthy counterparts. Natural compounds represent a large and readily-accessible library of bioactive structures that can be screened for synthetically lethal interactions by testing for the inhibition of kinases relevant to cancer cell survival. In this review, we discuss the concept of synthetic lethality and focus on scenarios in which natural compounds that target kinases may be applied to tip the balance in favor of cancer cell death during therapeutic challenge.
尽管已经取得了突破，但目前可用的癌症治疗方法在疗效和毒性方面仍存在重大未满足的需求。激酶抑制剂是一类靶向负责恶性细胞存活的信号因子的药物，可能至少可以解决其中的一些问题。合成致死性的概念为克服途径冗余提供了一个潜在的解决方案，它指的是在两种特定基因中的一种发生突变时，细胞仍然可以存活，而当两种基因同时发生突变时，细胞就会死亡的情况。当将其应用于癌症治疗时，在癌细胞中特异性上调的途径成为选择性靶点，对其健康对应物的脱靶毒性降低。天然化合物代表了一个庞大且易于获得的生物活性结构文库，可以通过测试与癌细胞存活相关的激酶的抑制作用来筛选合成致死性相互作用。在这篇综述中，我们讨论了合成致死性的概念，并重点讨论了靶向激酶的天然化合物可能应用于在治疗挑战中有利于癌细胞死亡的情况。
