Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
Curr Top Med Chem. 2019;19(23):2114-2127. doi: 10.2174/1568026619666190902145116.
The Ras proteins play an important role in cell growth, differentiation, proliferation and survival by regulating diverse signaling pathways. Oncogenic mutant K-Ras is the most frequently mutated class of Ras superfamily that is highly prevalent in many human cancers. Despite intensive efforts to combat various K-Ras-mutant-driven cancers, no effective K-Ras-specific inhibitors have yet been approved for clinical use to date. Since K-Ras proteins must be associated to the plasma membrane for their function, targeting K-Ras plasma membrane localization represents a logical and potentially tractable therapeutic approach. Here, we summarize the recent advances in the development of K-Ras plasma membrane localization inhibitors including natural product-based inhibitors achieved from high throughput screening, fragment-based drug design, virtual screening, and drug repurposing as well as hit-to-lead optimizations.
Ras 蛋白通过调节多种信号通路，在细胞生长、分化、增殖和存活中发挥重要作用。致癌突变型 K-Ras 是 Ras 超家族中最常突变的一类，在许多人类癌症中高度普遍存在。尽管人们为对抗各种 K-Ras 突变驱动的癌症进行了大量努力，但迄今为止，尚未批准任何有效的 K-Ras 特异性抑制剂用于临床。由于 K-Ras 蛋白的功能必须与其质膜相关联，因此靶向 K-Ras 质膜定位代表了一种合理且具有潜在可操作性的治疗方法。在这里，我们总结了 K-Ras 质膜定位抑制剂的最新进展，包括基于高通量筛选、基于片段的药物设计、虚拟筛选和药物再利用以及从命中到先导优化等方法获得的天然产物抑制剂。
