简介:乳腺癌是女性最常见的癌症,大约10-15%的新病例被归类为三阴性乳腺癌(TNBC)。传统的化疗通常对正常细胞有毒性。因此,重要的是发现靶向TNBC同时对正常细胞造成最小损伤的新抗癌化合物。受体酪氨酸激酶样孤儿受体1(ROR1)是一种在许多人类恶性肿瘤中过表达的癌胚蛋白,包括TNBC。本研究调查了靶向ROR1的潜在小分子。方法:使用AutoDockVina和Glide,我们筛选了70,000种化学物质进行调查。我们通过协商一致投票获得了10个代表性化合物,删除结构性警报,和聚类。手动评估后,选择化合物2和4进行MD模拟和细胞活力实验。化合物4在活力测定中显示出有希望的结果,这导致我们进一步进行细胞凋亡测定和免疫印迹。结果:化合物4(CID1261330)具有-6.635和-10.8的对接评分。它适合口袋,并显示与GLU64,ASP174和PHE93的相互作用。其RMSD在0.20nm附近波动并形成两个稳定的H键,表明化合物4的稳定性。它抑制MDA-MB-231,HCC1937和HCC1395细胞系中的细胞增殖,IC50值大约为2μM至10μM,分别。化合物4不杀死非恶性上皮乳腺细胞MCF-10A(IC50>27μM)。这些结果通过MDA-MB-231细胞中的大量凋亡细胞(47.6%)而不是MCF-10A细胞中的大量凋亡细胞(7.3%)得到证实。免疫印迹分析在相同方向上提供了额外的支持。讨论:这些发现共同表明化合物4具有有效消除TNBC细胞同时对正常乳腺细胞造成最小伤害的潜力。这项研究的有希望的结果为进一步测试化合物4在其他以ROR1上调为特征的恶性肿瘤中奠定了基础。作为其更广泛适用性的概念证明。
Introduction: Breast cancer is the most common cancer in women, with roughly 10-15% of new cases classified as triple-negative breast cancer (TNBC). Traditional chemotherapies are often toxic to normal cells. Therefore, it is important to discover new anticancer compounds that target TNBC while causing minimal damage to normal cells. Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is an oncofetal protein overexpressed in numerous human malignancies, including TNBC. This study investigated potential small molecules targeting ROR1. Methodology: Using AutoDock Vina and Glide, we screened 70,000 chemicals for our investigation. We obtained 10 representative compounds via consensus voting, deleting structural alerts, and clustering. After manual assessment, compounds 2 and 4 were chosen for MD simulation and cell viability experiment. Compound 4 showed promising results in the viability assay, which led us to move further with the apoptosis assay and immunoblotting. Results: Compound 4 (CID1261330) had docking scores of -6.635 and -10.8. It fits into the pocket and shows interactions with GLU64, ASP174, and PHE93. Its RMSD fluctuates around 0.20 nm and forms two stable H-bonds indicating compound 4 stability. It inhibits cell proliferation in MDA-MB-231, HCC1937, and HCC1395 cell lines, with IC50 values of approximately 2 μM to 10 μM, respectively. Compound 4 did not kill non-malignant epithelial breast cells MCF-10A (IC50 > 27 μM). These results were confirmed by the significant number of apoptotic cells in MDA-MB-231 cells (47.6%) but not in MCF-10A cells (7.3%). Immunoblot analysis provided additional support in the same direction. Discussion: These findings collectively suggest that compound 4 has the potential to effectively eliminate TNBC cells while causing minimal harm to normal breast cells. The promising outcomes of this study lay the groundwork for further testing of compound 4 in other malignancies characterized by ROR1 upregulation, serving as a proof-of-concept for its broader applicability.