Author: Zhong, Allen ; Malkoff, Nicolas ; Wang, Kasper S ; Asahina, Kinji ; Mahdi, Elaa ; Noriega, Nicolas ; Yeo, Theresa ; Short, Celia ; Xu, Jiabo ; Glazier, Alison

Background and Aims:Biliary atresia (BA), a congenital cholestatic liver disease, commonly culminates in end-stage liver disease. We previously demonstrated in BA that Prominin-1 (Prom1)-expressing hepatic progenitor cells (HPCs) expand within regions of developing fibrosis, giving rise to cholangiocytes within biliary ductular reactions. Null mutation of Prom1 or ablation of cells expressing Prom1 significantly diminishes fibrogenesis. FN14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), is expressed by HPCs. TWEAK/FN14 signaling promotes fibrosis in multiple organ systems. Therefore, we hypothesized that TWEAK/FN14 signaling mediates Prom1-expressing HPC proliferation leading to profibrogenic ductular reactions in BA.Approach and Results:The experimental mouse model of BA mediated by perinatal rhesus rotavirus (RRV) infection resulted in increased co-expression of Fn14 in Prom1-expressing HPCs within regions of ductular reactions. FN14 antagonist L524-0366 decreased ductular reactions, biliary fibrosis and periportal fibroblast activation in RRV injury. L524-0366 inhibition also demonstrated loss of downstream noncanonical NF-kB signaling expression in RRV injury. Murine HPC organoids demonstrated accelerated organoid growth and proliferation when treated with recombinant TWEAK. Increased organoid proliferation with recombinant TWEAK was lost when also treated with L524-0366. Analysis of a large publicly available RNA sequencing database of BA and normal control patients revealed significant increases in expression of PROM1, FN14, and genes downstream of TNF signaling and noncanonical NF-κB signaling pathways in BA infants. Infants who failed to achieve bile drainage after hepatoportoenterostomy had higher relative levels of FN14 expression.Conclusion:TWEAK/FN14 signaling activation in Prom1-expressing HPCs contributes to proliferation of profibrogenic ductular reactions in BA.

08 Jul 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure–Activity Relationship Analysis

Q1 · MEDICINE

Article

Author: Yang, Ming-Hui ; Chen, Yeh-Long ; Chen, Yi-Ming Arthur ; Chen, Marcelo ; Tzeng, Cherng-Chyi ; Tseng, Chih-Hua ; Tyan, Yu-Chang ; Kant, Rajni ; Chen, Wei-Cheng ; You, Kaiting ; Li, Wei-You ; Wang, Wen-Chieh ; Yen, Chia-Hung

Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.

01 Jul 2020·The Journal of ImmunologyQ2 · MEDICINE

Characterization of DNA Binding and Nuclear Retention Identifies Zebrafish IRF11 as a Positive Regulator of IFN Antiviral Response

Q2 · MEDICINE

Article

Author: Gui, Jian-Fang ; Gong, Xiu-Ying ; Zhao, Xiang ; Zhang, Yi-Bing ; Li, Yi-Lin ; Dan, Cheng

AbstractIn mammals, transcription factors of IFN-regulatory factors (IRFs) family translate viral recognition into IFN antiviral responses through translocating to nucleus and subsequently binding to the promoters of IFN and IFN-stimulated genes (ISGs). In addition to IRF1-9 conserved across vertebrates and IRF10 in teleost fish and bird, teleost fish has another novel member, IRF11; however, little is known about its role in IFN response. In this study, we provide evidence that IRF11 is present only in Osteichthyes (bony fish) but lost in tetrapods and subsequently characterize the stimulatory potential of zebrafish IRF11 to IFN antiviral response relevant to its subcellular localization and promoter binding. Overexpression of zebrafish IRF11 restricts virus replication through induction of IFN and ISGs. Zebrafish IRF11 is constitutively localized to nucleus, which is driven by a tripartite NLS motif, consisting of three interdependent basic clusters, two in DNA binding domain (DBD) and one in the region immediately C-terminal to DBD. Nuclear IRF11 binds to the IRF-binding element/IFN-stimulated response element motifs of zebrafish IFN promoters depending on the two conserved amino acids (K78, R82) within DBD helix α3. K78 and R82 also benefit zebrafish IRF11 nuclear import as two key residues positioned at the first basic cluster of the tripartite NLS motif. Such features enable zebrafish IRF11 to function as a positive transcription factor for fish IFN antiviral response. Our results identify a unique tripartite NLS motif that integrates DNA-binding activity and nuclear import ability, allowing zebrafish IRF11 to initiate IFN and ISG expression.

100 Deals associated with L-524-0366

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	US	Translational Genomics Research Institute	-

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