Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy.
Bicocca Center of Science and Technology for FOOD (BEST4FOOD), 20126 Milan, Italy.
Biomolecules. 2020 Nov 10;10(11):1535. doi: 10.3390/biom10111535.
genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources.
基因编码信号蛋白，在哺乳动物细胞中，这些蛋白作为分子开关，响应特定刺激，调节细胞增殖、生长、分化、存活、迁移和代谢等关键过程。Ras 功能失调对人类健康有重大影响：在一些发育障碍和 30%的所有人类癌症中，包括最致命的癌症中，都发现了基因的功能获得性点突变。因此，致病性 Ras 变体是重要的临床靶点，可以针对这些靶点开发新型、有效且可能具有选择性的药理学抑制剂。天然产物是结构上不同化合物的几乎无限资源，可以从中提取出用于此目的的化合物，因为从复杂来源中分离和筛选活性分子的方法得到了改进。在总结 Ras 蛋白的分子和调节特征以及与药物开发相关的 Ras 依赖性途径之后，我们指出了最有前途的抑制方法、野生型和致癌性 Ras 突变体的已知可成药位点，并描述了已知能够减弱 Ras 信号的天然化合物。最后，我们强调了从天然来源中选择潜在 Ras 抑制剂的关键问题和未来展望。
