Masum Abdullah-Al, Aoki Shin, Rahman Md Mahbubur, Hisamatsu Yosuke
Department of Pharmaceutical Sciences, North South University Bashundhara R/A Dhaka-1229 Bangladesh
Faculty of Pharmaceutical Sciences, Tokyo University of Science 2641 Yamazaki, Noda-shi Chiba 278-8510 Japan.
RSC Med Chem. 2024 Aug 1;15(11):3639-51. doi: 10.1039/d4md00183d.
Apoptosis is programmed cell death that eliminates undesired cells to maintain homeostasis in metazoan. Aberration of this process may lead to cancer genesis. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in cancer cells after ligation with death receptors (DR4/DR5) while sparing most normal cells. Therefore, strategies to induce apoptosis in cancer cells by mimicking the TRAIL emerge as a promising therapeutic tool. Hence, approaches are taken to develop TRAIL/DR-based cancer therapeutics. The recombinant soluble TRAIL (rhTRAIL) and death receptor agonistic antibodies were produced and tested pre-clinically and clinically. Pre-clinical and clinical trial data demonstrate that these therapeutics are safe and relatively well tolerated. But some of these therapeutics failed to exert adequate efficacy in clinical settings. Besides these biotechnologically derived therapeutics, a few chemically synthesized therapeutics are reported. Some of these therapeutics exert considerable efficacy and . In this review, we will discuss chemically synthesized TRAIL/DR-based therapeutics, their chemical and biological behaviour, design concepts and strategies that may contribute to further improvement of TRAIL/DR-based therapeutics.
细胞凋亡是一种程序性细胞死亡，可清除不需要的细胞以维持后生动物的体内平衡。这一过程的异常可能导致癌症发生。肿瘤坏死因子相关凋亡诱导配体（TRAIL）与死亡受体（DR4/DR5）结合后可诱导癌细胞凋亡，同时使大多数正常细胞免受影响。因此，通过模拟TRAIL来诱导癌细胞凋亡的策略成为一种有前景的治疗手段。因此人们采取了多种方法来开发基于TRAIL/DR的癌症治疗药物。重组可溶性TRAIL（rhTRAIL）和死亡受体激动性抗体已被生产出来，并进行了临床前和临床测试。临床前和临床试验数据表明，这些治疗药物是安全的，且耐受性相对良好。但其中一些治疗药物在临床环境中未能发挥足够的疗效。除了这些生物技术衍生的治疗药物外，还报道了一些化学合成的治疗药物。其中一些治疗药物具有相当的疗效。在这篇综述中，我们将讨论基于化学合成TRAIL/DR的治疗药物、它们的化学和生物学行为、设计理念以及可能有助于进一步改进基于TRAIL/DR的治疗药物的策略。
