Design, Synthesis, and Biological Evaluation of Chiral-Proline Derivatives as Novel HSP90 Inhibitors

Heat shock protein 90 (HSP90) is a promising target for oncology therapeutics. Over the past decades, several small molecule inhibitors have demonstrated significant antitumor activity in clinical trials. However, nearly all HSP90 inhibitors in clinical trials have failed due to toxicity or insufficient efficacy. By leveraging crystal structures and current knowledge, we synthesized and evaluated a series of novel derivatives with potent HSP90 inhibitory activity, optimized from resorcinol-based (<i>2R</i>, <i>4R</i>)-4-phenylproline. These derivatives underwent SAR analysis, leading to the discovery of compounds <b>16t</b> and <b>20m</b>, which exhibit strong HSP90 binding affinity and antiproliferative effects against MCF-7, HCT116, SKBr3, K562, and A549 cell lines. Nevertheless, further optimization of derivatives <b>16t</b> and <b>20m</b> was required to enhance their oral bioavailability and isoform selectivity. Our findings provide valuable insights for the ongoing research into selective HSP90α inhibitors and lay a foundation for developing next-generation HSP90α inhibitors and antitumor agents.