Discovery of <i>O</i>-Alkylamino-Tethered Niclosamide Derivatives as Potent and Orally Bioavailable Anticancer Agents

Abstract

Niclosamide has been identified to potently inhibit the activation, nuclear translocation, and transactivation of STAT3. Nevertheless, the poor aqueous solubility and bioavailability of niclosamide has hindered its further clinical development for cancer therapy. To discover new molecules with enhanced drug-like properties, a series of novel <i>O</i>-alkylamino tethered derivatives of niclosamide have been designed, synthesized, and biologically evaluated. Among them, compound <b>11</b> (<b>HJC0152</b>) has been demonstrated to significantly suppress MDA-MB-231 xenograft tumor growth <i>in vivo</i> (i.p. & p.o.), indicating its great potential as efficacious and orally bioavailable therapeutics for human cancer.