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癌症合成致死性的新视野：当前的发展和未来的展望。

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives.

机构信息

Computational & Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genova, Italy.

Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.

出版信息

J Med Chem. 2024 Jul 25;67(14):11488-11521. doi: 10.1021/acs.jmedchem.4c00113. Epub 2024 Jul 2.

DOI:10.1021/acs.jmedchem.4c00113
PMID:38955347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11284803/
Abstract

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADP-ribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular, molecular targets within DNA damage response have provided a source of inhibitors that have rapidly reached clinical trials. This Perspective focuses on the most recent progress in synthetic lethal targets and their inhibitors, within and beyond the DNA damage response, describing their design and associated therapeutic strategies. We will conclude by discussing the current challenges and new opportunities for this promising field of research, to stimulate discussion in the medicinal chemistry community, allowing the investigation of synthetic lethality to reach its full potential.

摘要

近年来，合成致死已被公认为癌症治疗的一种可靠模式。越来越多的合成致死靶点的发现，使得合成致死的应用范围大大扩展，远远超出了用于治疗 BRCA1/2 缺陷型肿瘤的聚（ADP-核糖）聚合酶抑制剂。特别是 DNA 损伤反应中的分子靶标为抑制剂的开发提供了源头，这些抑制剂迅速进入临床试验。本文着眼于 DNA 损伤反应内外的合成致死靶标及其抑制剂的最新进展，描述了它们的设计和相关的治疗策略。最后，我们将讨论这一极具前景的研究领域目前面临的挑战和新机遇，以激发药物化学界的讨论，使合成致死的研究能够充分发挥潜力。

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