Wang Haili, Li Chuchu, Liu Xiaoqing, Ma Mingliang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Shanghai University of Medicine & Health Sciences affiliated Zhoupu Hospital, Shanghai 201318, China.
Bioorg Med Chem. 2022 May 1;61:116707. doi: 10.1016/j.bmc.2022.116707. Epub 2022 Mar 18.
PI3K kinase plays an important role in regulating key processes in cells, such as cell growth, metabolism, proliferation, and apoptosis. The overexpression of PI3K kinase exists in many cancers. The proteolytic target chimera (PROTAC) technology is a new technology that uses the ubiquitin-proteasome system to degrade a given target protein. It has been described that CRBN-based PROTAC targets the degradation of PI3K kinase. However, PROTAC based on VHL has not been reported yet. Here, we connected the previously obtained highly active PI3K inhibitor to the VHL ligand through different small molecules, and obtained a series of PROTAC molecules targeting PI3K kinase. Obtain the most active compound through screening. It provides evidence for the feasibility of PROTAC technology to recruit VHL E3 ligase in PI3K kinase.
PI3K激酶在调节细胞中的关键过程，如细胞生长、代谢、增殖和凋亡中发挥着重要作用。PI3K激酶的过表达存在于许多癌症中。蛋白水解靶向嵌合体（PROTAC）技术是一种利用泛素-蛋白酶体系统降解特定靶蛋白的新技术。已有报道称基于CRBN的PROTAC靶向PI3K激酶的降解。然而，基于VHL的PROTAC尚未见报道。在此，我们通过不同的小分子将先前获得的高活性PI3K抑制剂与VHL配体连接，得到了一系列靶向PI3K激酶的PROTAC分子。通过筛选获得活性最高的化合物。这为PROTAC技术在PI3K激酶中招募VHL E3连接酶的可行性提供了证据。
