The Discovery of PLK4 Inhibitors: (<i>E</i>)-3-((1<i>H</i>-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents

TLDR

Polo‑like kinases regulate mitotic progression, and PLK4 has emerged as a promising anticancer target. Using ligand‑based virtual screening against a PLK4 homology model, the authors identified and optimized novel (E)-3‑(1H‑indazol‑6‑yl)methyleneindolin‑2‑ones, guided by computational models of the kinase domain and validated through kinase selectivity and cell‑cycle assays. The optimized compounds exhibit nanomolar PLK4 inhibition, potent antiproliferative effects, and in vivo efficacy in a xenograft model with CFI‑400437, underscoring their therapeutic promise.

Abstract

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.