Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
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.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: robert.mook@duke.edu.
Robert A
RA
Mook
Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
Jiangbo
J
Wang
Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
Xiu-Rong
XR
Ren
Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States.
Minyong
M
Chen
Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States; Duke Cancer Institute, PK/PD Core Laboratory, Durham, NC 27710, United States.
Ivan
I
Spasojevic
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States.
Larry S
LS
Barak
Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States.
H Kim
HK
Lyerly
Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: w.chen@dm.duke.edu.
Wei
W
Chen
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D009534:Niclosamide / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
D051153:Wnt Proteins; D051176:beta Catenin; D009534:Niclosamide
Cancer; Disease treatment; Niclosamide; Plasma concentration; Small molecule; Wnt signaling inhibitor; β-Catenin