Muñoz-Ayala Andrea, García-González Victor G, Pulido-Capiz Angel, Chimal-Vega Brenda, García-Villarreal Ruth A, Vique-Sánchez José L
School of Medicine Campus Mexicali, Autonomous University of Baja California, Mexicali, 21000, BC, México.
Int J Mol Cell Med. 2024;13(4):350-360. doi: 10.22088/IJMCM.BUMS.13.4.350.
The develop of new anticancer drug continues worldwide and one of the new therapeutic targets to reach it is Otubain 1 (OTUB1), since OTUB1 has functions related to prognosis in a variety of tumors and is strongly related to tumor proliferation, migration, and apoptosis by their functions on deubiquitinating. This study uses OTUB1´s active site to develop a specific pharmacological treatment to regulate the OTUB1 functions. The aim of this research was to evaluate the effects of ten compounds (OT1 - OT10), that previously were selected by molecular docking to develop a new anticancer drug to decrease the OTUB1 functions in the cancer processes. We evaluated the cytotoxic effect of OT1 - OT10 compounds on MCF-7, BT474 and MDA-MB 231 cells by MTT assay, and we determined characteristics of apoptosis by western blot analysis. Then, the best compound (OT5) was analyzed by molecular docking, molecular dynamics and theoretical toxicity for describing the interactions of OT5 compound with the OTUB1´s active site. We proposed that the OT5 compound has a high probability to be selective against OTUB1, with an apoptosis (regulating caspase-8) and cytotoxic effect on some cancer lines; IC50 for MCF-7: 97 µM and MDA-MB 231:147 µM, as well as we described that this compound could have specific interactions in the catalytic domain of OTUB1, modifying this protein's activity, decreasing the OTUB1 functions, and probably safe for humans. These results show the high potential of this compound for promoting the development of this compound as a new drug against cancer.
新型抗癌药物的研发在全球范围内持续进行，而奥图巴因1（OTUB1）是实现这一目标的新治疗靶点之一，因为OTUB1在多种肿瘤中具有与预后相关的功能，并且通过其去泛素化功能与肿瘤增殖、迁移和凋亡密切相关。本研究利用OTUB1的活性位点开发一种特定的药物治疗方法来调节OTUB1的功能。本研究的目的是评估十种化合物（OT1 - OT10）的效果，这些化合物先前通过分子对接被选中用于开发一种新型抗癌药物，以降低OTUB1在癌症过程中的功能。我们通过MTT法评估了OT1 - OT10化合物对MCF-7、BT474和MDA-MB 231细胞的细胞毒性作用，并通过蛋白质免疫印迹分析确定了细胞凋亡的特征。然后，通过分子对接、分子动力学和理论毒性分析了最佳化合物（OT5），以描述OT5化合物与OTUB1活性位点的相互作用。我们提出OT5化合物具有很高的选择性针对OTUB1的可能性，对某些癌细胞系具有凋亡（调节半胱天冬酶-8）和细胞毒性作用；对MCF-7的IC50为97μM，对MDA-MB 231为147μM，并且我们描述该化合物可能在OTUB1的催化结构域中具有特异性相互作用，改变该蛋白的活性，降低OTUB1的功能，并且可能对人类安全。这些结果表明该化合物在促进其作为一种新型抗癌药物的开发方面具有很高的潜力。
