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

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/ß-catenin signaling by decreasing the cytosolic levels of Dishevelled and ß-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/ß-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.

An update on psychotic spectrum disorders and disasters.

PURPOSE OF REVIEW: The aim of this study is to review the recent literature on disasters' impact on the course of psychotic spectrum disorders (PSDs) and how people with PSD fare during a disaster, including the effects of COVID-19. RECENT FINDINGS: Several, but not all, studies examining disasters including earthquake-affected communities and refugee populations have found increased incidence of PSDs. Studies have been inconsistent regarding psychosis incidence in COVID-19 patients. Meanwhile, patients with PSD have been found to cope poorly in recent disasters including flooding and a nuclear accident. Patients with schizophrenia appear to be at particular risk during COVID-19 due to such issues as poor awareness of health precautions and the psychiatric impact of lockdown. However, novel methods including telepsychiatry have allowed care of this population to remain consistent during COVID-19. SUMMARY: There is conflicting evidence as to the association between disasters and onset of PSD, and further study is needed to elucidate this link. Patients with PSDs are more likely to fare worse during disasters. Novel approaches to delivery of care have helped offset the psychiatric risks to PSD patients during the COVID-19 pandemic. These approaches may be applicable to other disaster scenarios or to general outpatient care.