The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458 United States.
The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458 United States.
ACS Chem Biol. 2023 Nov 17;18(11):2336-2342. doi: 10.1021/acschembio.3c00476. Epub 2023 Oct 23.
Protein-targeted small molecule medicines often bind RNAs and affect RNA-mediated pathways in cells. Historically, small molecule engagement and modulation of RNA have not been considered in medicine development; however, RNA should be considered both a potential on- and off-target. Kinase inhibitors have emecrged as common RNA binders with dovitinib, a classic receptor tyrosine kinase (RTK) inhibitor, inhibiting RTKs and the biogenesis of oncogenic microRNA-21 through direct engagement. In this study, we use knowledge of the molecular recognition of both protein and RNA targets by dovitinib to design molecules that specifically inhibit the RNA target but lack activity against canonical protein targets in cells. As it is now becoming apparent that RNA can be both an on- and off-target for small molecule medicines, this study lays a foundation to use design principles to maximize desired compound activity while minimizing off-target effects.
蛋白质靶向小分子药物通常与 RNA 结合，并影响细胞中的 RNA 介导途径。从历史上看，小分子与 RNA 的结合及其对 RNA 的调节在药物开发中并未被考虑；然而，RNA 既应该被视为潜在的靶标，也应该被视为潜在的脱靶。激酶抑制剂已成为常见的 RNA 结合物，达瓦替尼是一种经典的受体酪氨酸激酶 (RTK) 抑制剂，通过直接结合抑制 RTK 和致癌 microRNA-21 的生物发生。在这项研究中，我们利用达瓦替尼对蛋白质和 RNA 靶标的分子识别知识，设计出专门抑制 RNA 靶标但对细胞中典型蛋白质靶标无活性的分子。由于现在越来越明显的是，RNA 既可以是小分子药物的靶标，也可以是脱靶，这项研究为利用设计原则来最大化所需化合物的活性，同时最小化脱靶效应奠定了基础。
