Lei Wang

1. High-throughput screening (HTS), leveraging automated and miniaturized experimental systems, enables rapid assessment of the biological activity across large compound libraries and has long serv...

Conventional single-target drugs frequently suffer from limited efficacy and drug resistance. Here, we report an amphiphilic peptide dendrimer that integrates intrinsic bioactivity and nanocarrier functions, establishing a novel “drug-bioactive carrier” paradigm for multi-target cancer therapy. Using reverse molecular docking and limited proteolysis-mass spectrometry (LiP-MS), heat shock protein 90 (HSP90) was identified as a prominent candidate intracellular target of the dendrimer. Structure-activity relationship studies revealed that amphiphilic balance and dendrimer topology govern self-assembly and HSP90 modulation, with C16-KK2 displaying optimal activity by disrupting HSP90-CDC37 interaction and promoting degradation of oncogenic client proteins. Importantly, C16-KK2 nanoassemblies effectively encapsulate hydrophobic anticancer drugs, enhancing intracellular delivery and yielding synergistic therapeutic effects with rapamycin and sorafenib. In vivo, sorafenib-loaded C16-KK2 nanoparticles exhibited superior tumor accumulation and enhanced antitumor efficacy compared to free drug treatment. This work presents a mechanistically defined and structurally feasible bioactive nanocarrier platform, advancing rational design strategies for multi-target cancer therapeutics.

Proximity-inducing chimeras bring kinases or phosphatases into proximity with selected proteins to modulate phosphorylation. This review highlights recent advances in PHICSs and PHORCs and outlines key design challenges for phosphorylation control.

Small-molecule modulators targeting the N-terminal tetratricopeptide repeat (TPR) domain of protein phosphatase 5 (PP5) remain largely unexplored. Here, we report the repurposing of ilaprazole as a PP5 TPR domain binder identified via a fluorescence polarization-based competitive screen. Biophysical assays and molecular docking supported the interaction within the PP5 TPR binding pocket, revealing key structural features distinguishing ilaprazole from related proton pump inhibitors. In KRAS mutant colorectal cancer cells, ilaprazole engaged cellular PP5, leading to reduced RAF stability and suppressed mitogen-activated protein kinase (MAPK) signaling. While exhibiting minimal single-agent effects, ilaprazole sensitized cells to the MEK inhibitor binimetinib. These results validate the PP5 TPR domain as a druggable site and establish ilaprazole as a lead scaffold for pharmacological modulation of PP5-associated MAPK signaling.