Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
J Med Chem. 2023 Jul 27;66(14):10027-10035. doi: 10.1021/acs.jmedchem.3c00949. Epub 2023 Jul 17.
Cancer is a major public health concern requiring novel treatment approaches. Enzyme-instructed self-assembly (EISA) provides a unique approach for selectively inhibiting cancer cells. However, the structure and activity correlation of EISA remains to be explored. This study investigates new EISA substrates of alkaline phosphatase (ALP) to hinder ovarian cancer cells. Analogues were synthesized by modifying the amino acid residues of a potent EISA substrate that effectively inhibits the growth of OVSAHO, a high-grade serous ovarian cancer (HGSOC) cell line. The efficacy of against OVSAHO was assessed, along with the combination of substrate with clinically used drugs. The results reveal that substrate displays the highest cytotoxicity against OVSAHO cells, with an IC of around 8 μM. However, there was limited synergism observed between substrate and the tested clinically used drugs. These findings indicate that EISA likely operates through a distinct mechanism that necessitates further elucidation.
癌症是一个重大的公共卫生关注点，需要新的治疗方法。酶指导的自组装 (EISA) 为选择性抑制癌细胞提供了一种独特的方法。然而，EISA 的结构与活性相关性仍有待探索。本研究通过修饰一种有效抑制高等级浆液性卵巢癌 (HGSOC) 细胞系 OVSAHO 生长的强效 EISA 底物的氨基酸残基，研究了新的碱性磷酸酶 (ALP) 的 EISA 底物。合成了类似物 。评估了 对 OVSAHO 的功效，以及与临床使用药物联合使用的效果。结果表明，底物 对 OVSAHO 细胞显示出最高的细胞毒性，IC 约为 8 μM。然而，在 与测试的临床使用药物之间观察到的协同作用有限。这些发现表明 EISA 可能通过需要进一步阐明的独特机制起作用。
