Tsuji Kohei, Tamamura Hirokazu, Burke Terrence R
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health Frederick MD 21702 USA
Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University Tokyo 101-0062 Japan
RSC Chem Biol. 2024 Jun 4;5(8):721-728. doi: 10.1039/d4cb00031e. eCollection 2024 Jul 31.
The polo-like kinase 1 (Plk1) is an important cell cycle regulator that is recognized as a target molecule for development of anti-cancer agents. Plk1 consists of a catalytic kinase domain (KD) and a polo-box domain (PBD), which engages in protein-protein interactions (PPIs) essential to proper Plk1 function. Recently, we developed extremely high-affinity PBD-binding inhibitors based on a bivalent approach using the Plk1 KD-binding inhibitor, BI2536, and a PBD-binding peptide. Certain of the resulting bivalent constructs exhibited more than 100-fold Plk1 affinity enhancement relative to the best monovalent PBD-binding ligands. Herein, we report an extensive investigation of bivalent ligands that utilize the non-selective kinase inhibitor Wortmannin as a Plk1 KD-binding component. We found that bivalent ligands incorporating Wortmannin demonstrated affinity enhancements that could be similar to what we had obtained with BI2536 and that they could tightly bind to the protein. This suggests that these tight binding ligands might be useful for structural analysis of full-length Plk1.
Polo样激酶1（Plk1）是一种重要的细胞周期调节因子，被认为是抗癌药物开发的靶分子。Plk1由一个催化激酶结构域（KD）和一个polo盒结构域（PBD）组成，后者参与对Plk1正常功能至关重要的蛋白质-蛋白质相互作用（PPI）。最近，我们基于二价方法开发了具有极高亲和力的PBD结合抑制剂，该方法使用Plk1 KD结合抑制剂BI2536和一种PBD结合肽。某些所得的二价构建体相对于最佳的单价PBD结合配体表现出超过100倍的Plk1亲和力增强。在此，我们报告了对利用非选择性激酶抑制剂渥曼青霉素作为Plk1 KD结合成分的二价配体的广泛研究。我们发现，包含渥曼青霉素的二价配体表现出的亲和力增强可能与我们用BI2536获得的相似，并且它们可以紧密结合到该蛋白质上。这表明这些紧密结合的配体可能有助于全长Plk1的结构分析。
