Pyrazole-4-Carboxamide (YW2065): A Therapeutic Candidate for Colorectal Cancer via Dual Activities of Wnt/β-Catenin Signaling Inhibition and AMP-Activated Protein Kinase (AMPK) Activation

Abstract

Dysregulation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 (1c) which demonstrated excellent anti-CRC effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of β-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity. The anti-CRC effect of YW2065 was highlighted by its promising efficacy in a mice xenograft model.

RETRACTED: Pyrvinium Treatment Confers Hepatic Metabolic Benefits via β-Catenin Downregulation and AMPK Activation

“…In the present study, the transcript level of AXIN1 gene was not affected by pyrvinium treatment in hepatocytes. We have synthesized a variety of pyrvinium analogs [16,59]. Currently, our research focuses on the identification of a direct target that accounts for the effect of AXIN stabilization by pyrvinium and its analogs.…”

“…However, it might be not far away from the in vitro IC 50 in viability assays in hepatocytes. Using the chemical structure of pyrvinium as a template, we have synthesized and tested novel classes of analogs of which a lead compound has showed metabolic benefits against HFDinduced metabolic disorders [16,59]. With the mechanistic understanding of pyrvinium action in hepatic metabolism in the present study, we are aiming to develop pyrvinium analogs with better physicochemical, pharmacokinetic, and toxicological properties to explore their potential efficacy against various pathophysiological changes associated with hepatic metabolic disorders, including lipid accumulation, insulin resistance, glucose overproduction, and inflammation.…”

Phospholipase Cε Regulates Prostate Cancer Lipid Metabolism and Proliferation by Targeting AMP-Activated Protein Kinase (AMPK)/Sterol Regulatory Element-Binding Protein 1 (SREBP-1) Signaling Pathway

“…Recent studies have reported some genes, such as AMPK, can directly bind to or regulate SREBP-1 in lipid metabolism [ 21 , 44 ]. Moreover, some reports have suggested its critical role in some types of cancer [ 45 – 47 ], even in prostate cancer [ 18 , 48 ]. However, to the best of our knowledge, the function of AMPK in lipid metabolism of PCa has not been previously reported.…”

Calcium Permeable Channels in Cancer Hallmarks

“…In contrast, other pyrazol-based compounds such as GSK-7975A ( Derler et al., 2013 ), RO2959 ( Chen et al., 2013 ) and the carboxamide GSK1349571A ( Di Sabatino et al., 2009 ) seem to have reasonable selectivity with no affinity toward a wide range of receptors and ion channels and without affect TRPC1/5-mediated SOCE. Recently developed pyrazole analogues, such as, pyrazole-4-carboxamide (YW2065) and pyrimidine-2(1H)-thione derivative, have reported good anticancer activity in colorectal cancer cell lines compared to the standard drugs like sorafenib or oxaliplatin ( Fahmy et al., 2016 ; Yang et al., 2019 ). More detailed information about the pharmacology of various CRAC channels modulators is revised in recent reports ( Sweeney et al., 2009 ; Jairaman and Prakriya, 2013 ; Pevarello et al., 2014 ; Tian et al., 2016 ).…”