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%).
Sun et al. (Thu,) studied this question.