Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study

Kimura, Kiminori; Kanto, Tatsuya; Shimoda, Shinji; Harada, Kenichi; Kimura, Maiko; Nishikawa, Koji; Imamura, Jun; Ogawa, Eiichi; Saio, Masanao; Okusaka, Takuji; Inoue, Kazuaki; Ishikawa, Tetsuya; Ieiri, Ichiro; Kishimoto, Junji; Todaka, Koji; Kamisawa, Terumi

doi:10.1016/j.ebiom.2022.104069

Cited by 29 publications

(22 citation statements)

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“…The safety of PRI‐724 has been confirmed in a phase 1 study in patients with hepatitis C virus (HCV)–related cirrhosis [ 22 ] and in a current phase 1/2a study in patients with HCV and hepatitis B virus–related cirrhosis. [ 19 ] These findings suggest a therapeutic possibility for mitigating liver fibrosis progression in cholestatic liver diseases.…”

Section: Discussionmentioning

confidence: 96%

“…[ 17 ] PRI‐724 is highly tolerated as it does not inhibit P300/β‐catenin signaling, [ 18 ] and phase 1/2a clinical trials have confirmed that PRI‐724 does not have harmful effects on humans. [ 19 ] In this study, the efficacy of PRI‐724 in suppressing cholestatic liver fibrosis was evaluated in mice. Mouse models mimicking human PSC were established using three different methods: Mdr2 KO, BDL, and a 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine (DDC) diet.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of CBP/β‐catenin signaling ameliorated fibrosis in cholestatic liver disease

et al. 2022

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Chronic cholestatic liver diseases are characterized by injury of the bile ducts and hepatocytes caused by accumulated bile acids (BAs) and inflammation. Wnt/β-catenin signaling is implicated in organ fibrosis; however, its role in cholestatic liver fibrosis remains unclear. Therefore, we explored the effect of a selective cAMP response element-binding protein-binding protein (CBP)/β-catenin inhibitor, PRI-724, on murine cholestatic liver fibrosis. PRI-724 suppressed liver fibrosis induced by multidrug resistance protein 2 knockout (KO), bile duct ligation, or a 3.5-diethoxycarbonyl-1.4-dihydrocollid ine (DDC) diet; it also suppressed BA synthesis and macrophage infiltration.The expression of early growth response-1 (Egr-1), which plays a key role in BA synthesis, was increased in the hepatocytes of patients with cholestatic liver disease. PRI-724 inhibited Egr-1 expression induced by cholestasis, and adenoviral shEgr-1-mediated Egr-1 knockdown suppressed BA synthesis and fibrosis in DDC diet-fed mice, suggesting that PRI-724 exerts its effects, at least in part, by suppressing Egr-1 expression in hepatocytes. Hepatocytespecific CBP KO in mice suppressed BA synthesis, liver injury, and fibrosis,

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Inhibition of CBP/β‐catenin signaling ameliorated fibrosis in cholestatic liver disease

et al. 2022

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“…It should be noted that our study is focused on providing proof-of-principle for the reduction of the carcinogenic activation of CEGRs/ALCDs in aggressive HBL via β-catenin inhibition, rather than on the development of clinically effective and safe drug doses. In this regard, a recent report of a multicenter phase 1/2a trial for patients with cirrhosis found that low doses of PRI-724 significantly improved liver stiffness and reduced serum albumin levels, but not fibrosis [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-Mediated Activation of β-Catenin-TCF4-CEGRs/ALCDs Pathway Is an Essential Event in Development of Aggressive Hepatoblastoma

Gulati

Hanlon

Lutz

et al. 2022

Cancers

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Background and Aims: Hepatoblastoma (HBL), a deadly malignancy in children, is the most common type of pediatric liver cancer. We recently demonstrated that β-catenin, phosphorylated at S675 (ph-S675-β-catenin), causes pathological alterations in fibrolamellar hepatocellular carcinoma (FLC), by activating oncogenes and fibrotic genes via human genomic regions, known as cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs/ALCDs). The aim of this study was to determine the role of the ph-S675-β-catenin-TCF4-CEGRs/ALCDs pathway in HBL. Methods: The ph-S675-β-catenin-TCF4-CEGRs/ALCDs pathway was examined in a large cohort of HBL specimens, in HBL cell lines HepG2 and Huh6, and in patient-derived xenografts (PDXs). Results: β-catenin is phosphorylated at S675 in a large portion of tested HBL patients. In these patients, ph-S675-β-catenin forms complexes with TCF4 and opens CEGRs/ALCDs-dependent oncogenes for transcription, leading to a massive overexpression of the oncogenes. The inhibition of the β-catenin-TCF4-CEGRs/ALCDs axis inhibits the proliferation of cancer cells and tumor growth in HBL cell lines and HBL-PDXs. The ph-S675-β-catenin is abundant in mitotic cells. We found that markers of HBL Glypican 3 (GPC3) and Alpha Fetoprotein (AFP) are increased in HBL patients by β-catenin-TCF4-p300 complexes. Conclusions: The phosphorylation-mediated activation of the β-catenin-TCF4-p300-CEGRs/ALCDs pathway increases oncogene expression in patients with aggressive liver cancer and promotes the development of hepatoblastoma.

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“…An open-label, nonrandomized, multicenter phase 1/2a study recently showed that 3 had a potential antifibrotic effect without overt adverse events when intravenously injected at a dose of 280 mg/m 2 /4 h to 15 patients with HCV- and HBV-induced cirrhosis. Moreover, there was no increase in the area of reticular fibers in the hepatic lobule at 12 weeks . The most common adverse effects were diarrhea and nausea.…”

Section: Medicinal Chemistry Strategies For Discovering and Optimizin...mentioning

confidence: 96%

“…Moreover, there was no increase in the area of reticular fibers in the hepatic lobule at 12 weeks. 213 The most common adverse effects were diarrhea and nausea.…”

Section: Prodrug Strategymentioning

confidence: 99%

Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin’s Interactions with Its Nuclear Partners

et al. 2022

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Dysregulation of the Wnt/β-catenin signaling pathway is strongly associated with various aspects of cancer, including tumor initiation, proliferation, and metastasis as well as antitumor immunity, and presents a promising opportunity for cancer therapy. Wnt/β-catenin signaling activation increases nuclear dephosphorylated β-catenin levels, resulting in β-catenin binding to TCF and additional cotranscription factors, such as BCL9, CBP, and p300. Therefore, directly disrupting β-catenin’s interactions with these nuclear partners holds promise for the effective and selective suppression of the aberrant activation of Wnt/β-catenin signaling. Herein, we summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt β-catenin’s interactions with its nuclear binding partners. We discuss the challenges involved in developing drug-like inhibitors that target the interactions of β-catenin and its nuclear binding partner into therapeutic agents.

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Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study

Cited by 29 publications

References 35 publications

Inhibition of CBP/β‐catenin signaling ameliorated fibrosis in cholestatic liver disease

Inhibition of CBP/β‐catenin signaling ameliorated fibrosis in cholestatic liver disease

Phosphorylation-Mediated Activation of β-Catenin-TCF4-CEGRs/ALCDs Pathway Is an Essential Event in Development of Aggressive Hepatoblastoma

Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin’s Interactions with Its Nuclear Partners

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