State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Bioorg Chem. 2018 Dec;81:373-381. doi: 10.1016/j.bioorg.2018.08.028. Epub 2018 Aug 30.
Wogonin is a natural product isolated from the Scutellaria baicalensis and has been proved to be a potent and selective inhibitor of CDK9. Using this scaffold, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) targeting CDK9 by recruiting ubiquitin E3 ligase cereblon (CRBN). For constructing diverse Wogonin-based PROTACs, a "click chemistry" approach was employed for the synthesis of CDK9-targeting PROTACs. The results of western blotting assays showed that compounds containing triazole group in the linker could selectively downregulate the intracellular CDK9 level. Among these compounds, 11c could selectively degrade CDK9 in a concentration-dependent manner. In addition, the application of the proteasome inhibitor MG132 and CRBN siRNA silencing confirmed that 11c could promote the proteasome-dependent and CRBN-dependent degradation. Consistent with the degradation of the CDK9 protein, 11c selectively inhibits proliferation of CDK9-overexpressed cancer cells. Thus, our Wogonin-based PROTAC would be an efficient probe that induces the degradation of CDK9.
汉黄芩素是从黄芩中分离得到的天然产物，已被证明是一种有效的、选择性的 CDK9 抑制剂。我们利用这个支架，通过招募泛素 E3 连接酶 cereblon (CRBN)，设计并合成了一系列针对 CDK9 的蛋白水解靶向嵌合体 (PROTACs)。为了构建不同的基于汉黄芩素的 PROTACs，我们采用“点击化学”方法合成了针对 CDK9 的 PROTACs。Western blot 检测结果表明，连接子中含有三唑基团的化合物可以选择性地下调细胞内 CDK9 水平。在这些化合物中，11c 可以以浓度依赖的方式选择性地降解 CDK9。此外，蛋白酶体抑制剂 MG132 和 CRBN siRNA 沉默的应用证实，11c 可以促进蛋白酶体依赖和 CRBN 依赖的降解。与 CDK9 蛋白的降解一致，11c 选择性地抑制 CDK9 过表达的癌细胞的增殖。因此，我们基于汉黄芩素的 PROTAC 将是一种有效的诱导 CDK9 降解的探针。
