Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor–SN38 Conjugates for Targeted Drug Accumulation

Herein, a series of HSP90 inhibitor–SN38
conjugates through
ester and carbamate linkage in the 20-OH and 10-OH positions of SN38
were developed for improving the tumor-specific penetration and accumulation
of SN38 via extracellular HSP90 (eHSP90)-mediated
endocytosis. Mechanistic analyses confirmed that these novel conjugates
could bind to eHSP90 and be selectively internalized into the tumor
cells, which led to prolonged tumor regression in multiple models
of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including
acceptable HSP90α affinity and potent antitumor activity. Moreover,
compound 18b exhibited superior antitumor activity and
low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic
analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended
SN38 exposure at tumor sites. All these encouraging data indicate
that this compound is a promising new candidate for cancer therapy
and merits further chemical and biological evaluation.