Discovery of O-Alkylamino Tethered Niclosamide Derivatives as Potent and Orally Bioavailable Anticancer Agents

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 O-alkylamino tethered derivatives of niclosamide have been designed, synthesized, and biologically evaluated. Among them, compound 11 (HJC0152) has been demonstrated to significantly suppress MDA-MB-231 xenograft tumor growth in vivo (i.p. & p.o.), indicating its great potential as efficacious and orally bioavailable therapeutics for human cancer.