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更新于：2026-09-30
Tropifexor
更新于：2026-09-30
概要
基本信息
药物类型 小分子化药 |
别名 Tropifexor (USAN)、LJN-452、NVP-LJN452-NXA |
靶点 |
作用方式 激动剂 |
作用机制 FXR激动剂(胆汁酸受体FXR激动剂) |
在研适应症- |
非在研适应症 |
在研机构- |
最高研发阶段终止临床2期 |
首次获批日期- |
最高研发阶段(中国)终止 |
特殊审评- |
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结构/序列
分子式C29H25F4N3O5S |
InChIKeyVYLOOGHLKSNNEK-PIIMJCKOSA-N |
CAS号1383816-29-2 |
关联
8
项与 Tropifexor 相关的临床试验NCT04147195
NASH EXploratory Single and COmbination Treatment (NEXSCOT): An Open Label, Multicenter, Platform Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Various Single and Combination Treatments in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Who Manifest a Non-alcoholic Steatohepatitis (NASH)-Like Biomarker Phenotype
NCT04408937
A Randomized, Investigator and Subject Blinded, Multicenter, Parallel-arm Study to Determine the Safety and Tolerability of Tropifexor.
NCT04065841
A Randomized, Double-blind, Parallel-group, Multicenter Study to Assess Efficacy, Safety, and Tolerability of Oral Tropifexor (LJN452) & Licogliflozin (LIK066) Combination Therapy and Each Monotherapy, Compared With Placebo for Treatment of Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis.(ELIVATE)
100 项与 Tropifexor 相关的临床结果
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100 项与 Tropifexor 相关的转化医学
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100 项与 Tropifexor 相关的专利（医药）
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55
项与 Tropifexor 相关的文献（医药）2026-09-01ACCOUNTS OF CHEMICAL RESEARCH
Article
作者: Wang, Jun ; Li, Kan ; Tan, Bin
Conspectus:
SARS-CoV-2 papain-like protease (PLpro) is a compelling but historically underdeveloped antiviral target. Unlike the viral main protease (Mpro), which rapidly became the focus of intensive drug-discovery efforts and yielded clinical candidates and approved drugs, PLpro posed a more challenging medicinal chemistry problem: a shallow, flexible substrate-recognition surface and a mobile BL2 loop. Nevertheless, PLpro is a high-profile drug target because it is vital for viral replication by processing viral polyproteins and suppresses host innate immunity through deubiquitinating and deISGylating activities. These dual functions make PLpro more than a viral protease; it is a multifunctional immune-evasion enzyme whose inhibition could both block virus replication and restore antiviral host responses.This Account summarizes our group’s effort to convert PLpro from a challenging target into a tractable antiviral drug-discovery platform. We began by developing and applying orthogonal assays to identify specific PLpro inhibitors and triage false positives. High-throughput screening and drug-repurposing campaigns yielded early hits, including Jun9722, Jun9754, and tropifexor, but also revealed that biochemical inhibition alone was insufficient to predict cellular antiviral activity. This motivated us to develop a FlipGFP cell-based reporter assay as a BSL-2-compatible bridge between enzymology and live-virus studies. In addition, we later developed a fluorescence polarization assay using a fluorescein-labeled PLpro ligand to enable direct, high-throughput quantification of inhibitor binding. Together with FRET enzymatic assays, thermal shift experiments, cellular FlipGFP assays, and antiviral assays, these tools established a rigorous validation framework for PLpro medicinal chemistry.With this platform in place, we pursued structure-based PLpro inhibitor design. Early cocrystal structures showed that potent noncovalent inhibitors engage the BL2 groove and stabilize inhibitor-bound PLpro conformations. A major conceptual advance came from structural analysis of the Jun11313-bound PLpro complex, which revealed that an inhibitor substituent occupied a hydrophobic surface pocket corresponding to the Val70 position of ubiquitin. We designated this newly recognized region the Val70Ub pocket. Exploiting this pocket transformed PLpro inhibitor design by expanding ligand engagement beyond the canonical BL2 groove and enabling substantial gains in enzymatic inhibition and antiviral activity.This design principle led to orally active noncovalent inhibitors, including Jun12682 and the quinoline lead Jun13296, both of which showed potent enzymatic inhibition, cellular antiviral activity, favorable mouse pharmacokinetics, and protection in SARS-CoV-2 mouse infection models. We further extended the Val70Ub-centered recognition strategy to covalent inhibitor design by appending cysteine-reactive warheads (covalent electrophiles) to optimized noncovalent scaffolds, thereby generating compounds that retained BL2 groove and Val70Ub binding while engaging the catalytic Cys111. Finally, resistance studies identified E167, Y268, and Q269 as drug resistance hotspots, highlighting the need to design inhibitors that engage less mutation-sensitive binding sites.Overall, this Account illustrates how integrated assay development, structural biology, medicinal chemistry, pharmacology, virology, and resistance analysis can transform a challenging viral deubiquitinase into a credible antiviral target. The lessons from PLpro should inform future efforts to design broad-spectrum coronavirus PLpro inhibitors and to target other viral protease–deubiquitinase enzymes with shallow, flexible binding surfaces.
2026-08-01CANCER LETTERS
Bile acid retention impairs tumoral antigen presentation and intrinsic tumor suppression in MASH-HCC
Article
作者: Wang, Jiabei ; Wei, Wei ; Ma, Jinhu ; Sun, Linmao ; Liu, Yufeng ; Zhao, Xueping ; Deng, Shumin ; Duan, Jiawei ; Zhang, Zhongyuan
Metabolic reprogramming enables tumor cells to evade immune surveillance, yet the mechanisms linking specific metabolic alterations to immune evasion remain incompletely understood. We found that in metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) cells, aberrant accumulation of bile acids impairs the NOD-like receptor family CARD domain containing 5-mediated major histocompatibility complex class I antigen presentation pathway, thereby leading to loss of antigenicity in tumor cells. Bile acid retention in tumor cells results primarily from the downregulation of the efflux pump ABCB11, driven by G protein-coupled receptor 120-mediated FXR suppression under lipid-rich conditions. Furthermore, genetic inactivation of NLRC5 abolishes the recovery of MHC-I expression and antitumor immunity upon bile acid reduction. Treatment with Tropifexor, a potent selective FXR agonist, synergizes with immune checkpoint blockade, significantly reducing tumor burden and potentiating the intratumoral adaptive immune response in mice. Thus, we reveal that intracellular bile acid accumulation suppresses both tumor antigenicity and intrinsic antitumor immunity. This insight provides a therapeutic target for improving immunotherapy outcomes in MASH-HCC.
2026-03-01ALIMENTARY PHARMACOLOGY & THERAPEUTICS
Clinical trial: A Phase 2 Randomised Platform Study to Assess Monotherapy and Combination Treatment Regimens in Metabolic Dysfunction–Associated Steatohepatitis
Article
作者: Frias, Juan ; Zack, Julia ; Drakeford, Clive ; Yadav, Brijesh ; Zhang, Yiming ; Ukomadu, Chinweike ; Lawitz, Eric ; Zhou, Heng ; Badman, Michael K. ; Schmouder, Robert ; Greenbaum, Linda E. ; Weiss, H. Markus ; Naoumov, Nikolai V. ; Koo, Phillip ; Martic, Miljen
ABSTRACT:
Background:
Drug combinations have potential for additive or synergistic efficacy in patients with metabolic dysfunction–associated steatohepatitis (MASH).
Aim:
To assess the safety, efficacy and pharmacokinetics of single or combination treatments in patients with MASH.
Methods:
In this multicentre, open‐label, platform phase 2 study, patients (
N
= 41) were randomised 1:1 to LYS006 20 mg twice‐daily (bid) monotherapy or LYS006 20 mg bid+tropifexor 200 μg once‐daily (qd) combination therapy for 12 weeks. The primary endpoint was safety; secondary endpoints were efficacy and pharmacokinetics.
Results:
Pruritus adverse events (AEs) were reported in 62% of patients in the combination arm. Other AEs were similar between the treatment arms. A greater reduction in alanine aminotransferase (ALT) and liver fat was observed in the combination versus monotherapy arm (ALT: 43% vs. 13% reduction; liver fat: 37% vs. 20% reduction, respectively). No significant impact on biomarkers for liver fibrosis was observed in either treatment arm, but there was an indication for lower plasma exposure to LYS006 upon co‐administration with tropifexor.
Conclusions:
LYS006 20 mg bid monotherapy and LYS006 20 mg bid+tropifexor 200 μg qd therapy were well tolerated with the exception of a high frequency of pruritus in the combination arm, consistent with the now known pharmacologic effect of farnesoid X receptor agonists. The greater reductions in ALT and liver fat in the combination arm versus monotherapy arm were similar to those observed with tropifexor as monotherapy in a previously reported phase 2 clinical trial, and clear additional benefit was not observed in combination treatment with LYS006. This study design allowed for rapid screening of potentially high efficacy drug combinations in MASH.
Trial Registration:
ClinicalTrials.gov
identifier: NCT04147195
64
项与 Tropifexor 相关的新闻（医药）2026-09-16
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100 项与 Tropifexor 相关的药物交易
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外链
| KEGG | Wiki | ATC | Drug Bank |
|---|---|---|---|
| D11548 | Tropifexor | - |
研发状态
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 肝纤维化 | 临床2期 | 美国 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 阿根廷 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 比利时 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 加拿大 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 捷克 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 埃及 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 法国 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 德国 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 印度 | 2018-09-11 | |
| 肝纤维化 | 临床2期 | 以色列 | 2018-09-11 |
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临床结果
临床结果
适应症
分期
评价
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临床2期 | 350 | 網鏇顧衊壓夢積遞醖窪(網衊齋襯壓獵鏇構醖齋) = 鹹獵觸窪構憲齋鹹積衊 艱鑰觸蓋鏇鏇鹹憲淵獵 (膚廠願醖衊鹹網襯餘製 ) 更多 | - | 2023-02-16 | |||
Placebo | 網鏇顧衊壓夢積遞醖窪(網衊齋襯壓獵鏇構醖齋) = 糧夢壓獵築遞願蓋顧餘 艱鑰觸蓋鏇鏇鹹憲淵獵 (膚廠願醖衊鹹網襯餘製 ) 更多 | ||||||
临床2期 | 61 | 醖夢網繭衊餘顧鏇製餘(糧鑰廠淵選鑰鑰構鹽憲) = 壓鑰廠製鹽艱製顧築淵 範衊簾範衊鹹構壓鏇觸 (鑰選膚糧膚願醖鑰網廠 ) 更多 | 积极 | 2022-07-21 | |||
Placebo | 醖夢網繭衊餘顧鏇製餘(遞獵淵夢簾鹹範淵積網) = 膚淵蓋範築繭鏇餘鹹選 製鏇繭衊構鬱網鹹鏇鏇 (蓋糧築觸醖鹹淵窪窪簾 ) | ||||||
临床2期 | 20 | 餘淵廠製齋夢鏇築繭鬱(醖衊廠鑰願選網鏇憲窪) = 顧簾襯鹽膚築鹽鏇顧淵 顧簾顧遞顧構遞簾鑰網 (醖蓋憲淵憲淵範窪鬱襯 ) | 积极 | 2020-09-01 | |||
Placebo | 餘淵廠製齋夢鏇築繭鬱(醖衊廠鑰願選網鏇憲窪) = 廠鬱鹹衊鹹觸襯積鹽齋 顧簾顧遞顧構遞簾鑰網 (醖蓋憲淵憲淵範窪鬱襯 ) | ||||||
临床2期 | 20 | (LJN452 ALL Patients) | 襯觸衊餘鬱憲築衊構顧 = 築夢醖願鏇醖齋襯繭醖 願遞襯製蓋顧繭壓淵蓋 (夢衊齋醖構艱獵構齋願, 製廠膚觸淵鬱餘窪鑰憲 ~ 遞壓鑰獵簾艱繭醖艱願) 更多 | - | 2019-05-01 | ||
Placebo (Placebo ALL Patients) | 襯觸衊餘鬱憲築衊構顧 = 膚觸繭遞遞積憲構築憲 願遞襯製蓋顧繭壓淵蓋 (夢衊齋醖構艱獵構齋願, 餘鑰鑰憲獵選鹽鹹憲壓 ~ 膚選遞蓋窪鑰衊鑰醖壓) 更多 | ||||||
临床2期 | 42 | 顧壓糧餘觸鏇鹹鹹選憲(廠觸積鏇蓋醖窪鏇鏇廠) = 顧膚餘鹽製鹽鹹簾鏇鏇 鬱簾壓蓋衊顧選簾簾願 (獵襯構鹹鬱築構製鏇積 ) | - | 2019-01-03 |
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