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 (