The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including
cancer. We previously reported the FDA-approved
anthelmintic drug Niclosamide inhibits Wnt/β-
catenin signaling and suppresses
colon cancer cell growth in vitro and in vivo.
Niclosamide is a multi-functional
drug that possesses important
biological activity in addition to inhibition of Wnt/β-
catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and
salicylamide region of
Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or
chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl
amides and reverse
amide derivatives lost significant potency, while acylated
salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives.
Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of
Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of
Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of
Niclosamide and Wnt-signaling inhibitors based on the
Niclosamide chemotype. The identification of novel derivatives of
Niclosamide that metabolize to
Niclosamide and increase its
drug exposure may provide important research tools for in vivo studies and provide
drug candidates for treating
cancers with dysregulated Wnt signaling including
drug-resistant
cancers. Moreover, since
Niclosamide is a multi-functional
drug, new research tools such as DK520 could directly result in novel treatments against bacterial and
viral infection, lupus, and
metabolic diseases such as type II diabetes, NASH and
NAFLD.