Discovery of Novel Hsp90 Inhibitor-Evodiamine Derivative Conjugates as Potent and Orally Active Antitumor Agents for Colon Cancer Therapy

  • J Med Chem. 2026 May 28. doi: 10.1021/acs.jmedchem.5c02943.
Yuhang Sun  1 ,  Keliang Li  2 ,  Hua Sun  1 ,  Changlu Li  3 ,  Jie Su  1 ,  Yuhong Shang  1 ,  Liangsiyu Zhang  1 ,  Yutong Zhu  1 ,  Haoyu Li  1 ,  Chunquan Sheng  1 ,  Shanchao Wu  1
Affiliations
  • 1. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
  • 2. Health Service Department of the Guard Bureau of the Joint Staff Department, Beijing 100017, China.
  • 3. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
PMID: 42207984 DOI: 10.1021/acs.jmedchem.5c02943
Abstract

Natural products (NPs) and their derivatives have long been important components of antitumor drugs. Nevertheless, traditional natural product derivatives are generally limited by tumor-targeting deficiency and toxicity to normal tissue. Particularly, there remains a lack of effective strategies to improve in vivo antitumor efficacy and reduce the toxicity of natural product derivatives. Herein, a series of heat shock protein 90 (HSP90) inhibitor-evodiamine (an NP from Evodiae fructus) conjugates were rationally designed, binding extracellular HSP90 (eHsp90), which could mediate endocytosis to improve the antitumor efficacy of evodiamine derivatives. Notably, conjugate 5a demonstrated a potent antitumor efficacy. It exhibited significant in vitro antiproliferative activity (IC50 = 7.7 nM) and high HSP90 inhibitory activity (IC50 = 19.4 nM). Furthermore, conjugate 5a achieved excellent in vivo tumor growth inhibition upon intraperitoneal injection (12 mg/kg; TGI = 72.9%) and oral administration (24 mg/kg; TGI = 61.2%).

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