Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth

Abstract

The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide’s anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.

Niclosamide-induced Wnt signaling inhibition in colorectal cancer is mediated by autophagy

“…Despite the clear rationale for inhibiting the Wnt/β-catenin pathway in colorectal cancer, developing effective strategies to intervene in this pathway clinically has proven challenging (1,3). Through a high-content drug screen, we previously discovered the approved anthelmintic drug niclosamide as an inhibitor of the Wnt pathway (4) and have developed several niclosamide derivatives with improved pharmacological properties to overcome its low bioavailability and poor systemic exposure, including a nanoparticle formulation of a niclosamide conjugate (7,11,25). However, the clinical use of niclosamide and its derivatives to treat systemic diseases such as cancer, requires a more detailed understanding of the mechanism of its drug action.…”

“…We were the first to discover niclosamide, an FDA-approved anthelmintic drug, as a novel inhibitor of Wnt/β-catenin signaling (4). Subsequently, we found that niclosamide and its derivatives have anticancer effects in colorectal cancer cells both in vitro and in vivo, without observable toxicity (5)(6)(7)(8)(9)(10)(11).…”

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

“…DK419 is a derivative of niclosamide with multifunctional activity and improved pharmacokinetic properties. It is a promising drug for the treatment of colorectal cancer and Wnt-related diseases [ 256 ]. Inhibition of Wnt secretion by blocking the acidification of an important post-translational modification of palmitoleic provides a useful therapeutic intervention.…”

Benchmarking Small-Dataset Structure-Activity-Relationship Models for Prediction of Wnt Signaling Inhibition

“…To the best of our knowledge, there has been a total of 70 drug compounds available in literature with experimentally validated effectiveness for internalizing Frizzled receptor proteins, and thus inhibiting Wnt signaling in human U2OS cells [21], [27]- [29]. Specifically, all these 70 compounds have been classified as active [inactive] compounds if they were able [unable] to induce the internalization of Frizzled receptor proteins, according to the cell imaging data from before and after applying the compound to the cell culture.…”

“…Some of these diseases (e.g., lung cancer) are associated with altered function/levels of proteins in specific Wnt/-catenin pathways (one type of Wnt signaling pathway), which lead to elevated gene expression that influences cell proliferation and survival [21]. For this reason, inhibition of Wnt/-catenin signaling by small molecule modulators (e.g., Niclosamide) is being considered and developed as a candidate cancer treatment [21], [26]- [29]. For instance, screening assays based on live cell imaging have been used to identify Wnt/-catenin inhibitors [30].…”