62790-50-5Relevant articles and documents
Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth
Wang, Jiangbo,Mook, Robert A.,Ren, Xiu-rong,Zhang, Qingfu,Jing, Genevieve,Lu, Min,Spasojevic, Ivan,Lyerly, H. Kim,Hsu, David,Chen, Wei
, p. 5435 - 5442 (2018)
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.
CHEMICAL MODULATORS OF IMMUNE CHECKPOINTS AND THERAPEUTIC USE
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Paragraph 0242, (2017/07/29)
Compounds and pharmaceutical compositions that down-regulate immune checkpoints such as PD-1, PD-L1 and CTLA-4 are provided. Also provided are methods of treating a disease by down-regulating immune checkpoints such as PD-1, PD-L1 and CTLA-4. The methods
Broad spectrum chemistry as practised by Novartis process research
Mickel, Stuart J.,Fischer, Reto,Marterer, Wolfgang
, p. 640 - 648 (2007/10/03)
Three actual examples from the current product palette within Novartis Process Research will demonstrate the some of the variety and challenges encountered in modern chemical development.