Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin 9016, New Zealand.
J Med Chem. 2021 Dec 23;64(24):18114-18142. doi: 10.1021/acs.jmedchem.1c01609. Epub 2021 Dec 8.
Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene Synthetic lethal (SL) vulnerabilities arising from dysfunction represent attractive targets for drug development. Recently, SLEC-11 () emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize . Overall, 63 analogues were synthesized and tested for their SL activity toward isogenic mammary epithelial -deficient cells (MCF10A-). Among the 26 compounds with greater cytotoxicity, AL-GDa62 () was four-times more potent and more selective than with an EC ratio of 1.6. Furthermore, preferentially induced apoptosis in cells, and mammary and gastric organoids were significantly more sensitive to at low micromolar concentrations. Thermal proteome profiling of treated MCF10A cell protein lysates revealed that specifically inhibits TCOF1, ARPC5, and UBC9. , inhibited SUMOylation at low micromolar concentrations.
弥漫性胃癌和乳腺小叶癌是侵袭性恶性肿瘤，常与肿瘤抑制基因失活突变有关。功能障碍导致的合成致死（SL）脆弱性代表了药物开发的有吸引力的靶点。最近，SLEC-11()在 E-钙黏蛋白缺陷细胞中成为 SL 先导。在这里，我们描述了优化的努力。总的来说，合成并测试了 63 种类似物对同源乳腺上皮缺陷细胞（MCF10A-）的 SL 活性。在具有更高细胞毒性的 26 种化合物中，AL-GDa62()比 更有效且选择性更高，EC 比值为 1.6。此外， 优先诱导 细胞凋亡，并且 乳腺和胃类器官在低微摩尔浓度下对 更敏感。用处理的 MCF10A 细胞蛋白裂解物进行的热蛋白质组学分析表明， 特异性抑制 TCOF1、ARPC5 和 UBC9。 ，在低微摩尔浓度下抑制 SUMO 化。
