Recent Patents on Anti-Cancer Drug Discovery ( IF 2.8 ) Pub Date : 2021-10-31 , DOI: 10.2174/1574892816666210509001139 Veera V Shivaji R Edupuganti 1 , Joel D A Tyndall D A Tyndall 1 , Allan B Gamble 1
Background: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. The key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety.
Objective: Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells.
Methods: In this review, an integrated view of the potential use of prodrugs and ADCs in cancer treatment are provided. This review presents recent patents and related publications over the past ten years uptill 2020.
Results: The recent patent literature has been summarised for a wide variety of self-immolative PABC linkers, which are cleaved by factors including responding to the difference between the extracellular and intracellular environments (pH, ROS, glutathione) through over-expressed enzymes (cathepsin, plasmin, β-glucuronidase) or bioorthogonal activation. The mechanism for self-immolation involves the linker undergoing a 1,4- or 1,6-elimination (via electron cascade) or intramolecular cyclisation to release cytotoxic drug at the targeted site.
Conclusion: This review provides the commonly used strategies from recent patent literature in the development of prodrugs based on targeted cancer therapy and antibody-drug conjugates, which show promise in therapeutic applications.
中文翻译:
癌症治疗中前药和抗体药物偶联物中的自我牺牲接头
背景:设计具有高抗肿瘤功效和降低毒性的抗癌疗法仍然具有挑战性。可以特异性和有效地将细胞毒性化合物递送至癌细胞的抗癌前药和抗体-药物-偶联物 (ADC) 策略已被用于克服一些挑战。许多这些策略成功的关键是一个自我牺牲的连接器,它在激活后可以释放药物有效载荷。各种类型的可触发自牺牲接头用于前药和 ADC,以提高其疗效和安全性。
目的:大量专利报道了前药和 ADC 中的自我牺牲接头在癌症治疗中的重要性。基于最近的专利文献,我们总结了设计位点特异性激活无毒前药和 ADC 的方法,以提高杀伤癌细胞的选择性。
方法:在本综述中,提供了前药和 ADC 在癌症治疗中潜在用途的综合观点。本综述介绍了截至 2020 年的过去十年中的最新专利和相关出版物。
结果:最近的专利文献总结了多种自我牺牲的 PABC 接头,这些接头通过过度表达的酶(组织蛋白酶)响应细胞外和细胞内环境(pH、ROS、谷胱甘肽)之间的差异等因素进行切割、纤溶酶、β-葡萄糖醛酸酶)或生物正交激活。自焚机制涉及接头经历 1,4-或 1,6-消除(通过电子级联)或分子内环化以在靶位释放细胞毒性药物。
结论:本综述提供了近期专利文献中用于开发基于靶向癌症治疗和抗体-药物偶联物的前药的常用策略,这些策略在治疗应用中显示出前景。