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phenylbutyrate (Luc01 / Luc 01 / Pheburane)

✓ Approved

Duchesnay Inc. · 小分子 · 小分子

什么是 phenylbutyrate？

phenylbutyrate 是一种小分子，由Duchesnay Inc.研发。该药已获批，用于治疗相关适应症，给药途径：Oral (PO)。

药物档案

商品名Luc01, Luc 01, Pheburane
公司Duchesnay Inc.
药物类别小分子
给药途径Oral (PO)
状态Approved
来源： ClinicalTrials.gov, Duchesnay Inc.

治疗适应症

phenylbutyrate 针对 4 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Congenital, familial and genetic disordersOrnithine transcarbamoylase deficiency✓ Approved
Congenital, familial and genetic disordersCarbamoyl phosphate synthetase deficiency✓ Approved
Congenital, familial and genetic disordersArgininosuccinate synthetase deficiency✓ Approved
Congenital, familial and genetic disordersUrea cycle disorder✓ Approved

相关研究文献

PubMedAmerican journal of physiology. Gastrointestinal and liver physiology2026-08-05

Contrasting Impacts of Two ABCB11 Variants Affecting the Same Residue in Progressive Familial Intrahepatic Cholestasis Type 2.

Riahi Yosra Y, Almes Marion M, Banet Manon M, Mareux Elodie E et al.

Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2) is a severe autosomal recessive cholestatic liver disease due to variations in ABCB11. Clinical and molecular consequences of two missense variations affecting the same ABCB11 residue (T463) were characterized, and pharmacological strategies were investigated. Clinical and genetic data were collected from two PFIC2 patients carrying p.T463I or p.T463P substitution. A three-dimensional (3D) structure analysis was performed to predict substitution impacts. ABCB11T463I and ABCB11T463P variants were expressed in HepG2 and Madin-Darby canine kidney cells to assess their subcellular localization and functional activity. Pharmacological modulators were tested to correct the defects. The patient carrying ABCB11T463I exhibited a mild phenotype and responded to surgical biliary diversion. Conversely, the patient carrying ABCB11T463P required a liver transplantation before age one. 3D structure and in vitro analyses predicted a functional defect in both variants, and a folding defect for the T463P variant. In vitro, ursodeoxycholic acid combined with glycerol phenylbutyrate increased ABCB11T463P canalicular expression (40.2 ± 7.7% of the wild-type, p <0.0001) and improved transport activity (32.4 ± 10.3% of the wild-type, p <0.0001). VX-770 and SBC040 increased ABCB11T463I function from 37.9 ± 2.5% (DMSO) to 73.2 ± 12.3% and 76.1 ± 17.5%, respectively, of the wild-type activity (p <0.0001). ABCB11 missense variations, even affecting the same residue, can cause various molecular defects, resulting in mild to severe phenotypes. 3D structure and in vitro analyses could be used to predict the severity of missense variants and guide the treatment of PFIC2 patients with pharmacological modulators.

PMID 42552878
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PubMedBiological & pharmaceutical bulletin2026-07-30

A Phenylbutyrate-Derived Nitric Oxide Donor Induces Pancreatic Cancer Cell Death Accompanied by Impairment of Autophagy-Related Pathways and HIF-1α Reduction.

Takasaki Kaho K, Beppu Takuro T, Imoto Shuhei S, Tsukigawa Kenji K et al.

4-[4-(Bis(2-(nitrooxy)ethyl)amino)phenyl]butanoic acid (NPB), a phenylbutyrate-derived nitric oxide (NO) donor, has been developed as a potential anticancer agent for pancreatic cancer. In the present study, we investigated the cytotoxic effects of NPB under cellular stress conditions and examined its effects on autophagy-related pathways and hypoxia-inducible factor-1α (HIF-1α) signaling. NPB-induced cell death was enhanced under nutrient-deprived conditions in PANC-1 cells. In addition, NPB induced greater cell death under hypoxic conditions than under normoxic conditions in PANC-1 cells, whereas in BxPC-3 cells, NPB-induced cell death was slightly but significantly lower under hypoxic conditions than under normoxic conditions. Using GFP-LC3-RFP-LC3ΔG reporter cells, NPB suppressed starvation-induced autophagic flux. In pancreatic cancer cells, NPB decreased DAPGreen fluorescence, an indicator of autophagy-related vesicular activity, and increased propidium iodide-positive cells under hypoxic conditions. Western blot analysis showed that NPB induced the accumulation of p62 and LC3 under both normoxic and hypoxic conditions. Under hypoxic conditions, NPB also reduced HIF-1α expression. Under cobalt chloride (CoCl2)-induced HIF-1α-accumulating conditions, NPB and the NO donor NONOate suppressed HIF-1α expression, whereas OH-PB, a non-NO-releasing analog, showed little effect. Furthermore, the proteasome inhibitor MG132 restored HIF-1α accumulation in NPB-treated cells. Time-course analysis under CoCl2-treated conditions showed that NPB reduced HIF-1α expression concomitantly with p62 accumulation. These findings suggest that NPB induces pancreatic cancer cell death, particularly under nutrient-deprived and hypoxic conditions, accompanied by impairment of autophagy-related pathways and NO-dependent, proteasome-associated reduction of HIF-1α.

PMID 42528222
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PubMedFrontiers in oncology2026-07-29

Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming.

Omene Egiroh E

Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide. Treatment failure is driven in large part by a profoundly immunosuppressive tumour microenvironment (TME) in which metabolic competition between GBM cells, bone marrow-derived immunosuppressive myeloid cells, and cytotoxic T lymphocytes determines cellular dominance. This review frames the GBM TME through the lens of metabolic cell competition: a process by which differential metabolic fitness, mediated principally through glucose and glutamine consumption, establishes a suppressive hierarchy that forecloses effective anti-tumour immunity. Aerobic glycolysis in GBM cells produces lactate, which polarises tumour-associated macrophages toward immunosuppressive phenotypes via GPR81/HIF-1alpha signalling and directly impairs T cell effector function through extracellular acidification and competition for monocarboxylate transporter capacity. GBM cells and immunosuppressive myeloid cells cannot sustain their proliferative and immunosuppressive programmes without glucose and glutamine; cytotoxic memory T cells, whose effector functions are energetically but not biosynthetically demanding, retain the capacity to function through fatty acid oxidation when these substrates are restricted. Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit. Pharmacological ketosis elevates beta-hydroxybutyrate, an endogenous HDAC inhibitor that further augments T cell effector function through NLRP3 inflammasome suppression. The mechanistic and clinical evidence for each intervention is reviewed, metabolic engineering strategies for increasing T cell competitive fitness are described, and principal research gaps are identified. GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent competitive coalition whose simultaneous disruption is the central therapeutic proposition reviewed. Evidence is synthesised from in vitro metabolic competition experiments, immune-competent murine GBM models, mechanistic pharmacology studies, and early-phase clinical pharmacodynamic data in human GBM.

PMID 42523684
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PubMedActa pharmacologica Sinica2026-07-28

SERCA2 gatekeeper role in aortic autophagy: targeting the Ca2+-mTOR axis to prevent aortic dissection.

Wang Lang-Tao LT, Chen Xun X, Song Jia-Rou JR, Liu Jun-Cai JC et al.

Aortic dissection (AD) is a catastrophic cardiovascular syndrome with an in-hospital mortality of more than 90%. We previously identified oxidative inactivation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) at cysteine 674 (C674) as a driver of aortic smooth muscle cell (ASMC) phenotypic switching. However, its causal impact on autophagic flux and AD remains unresolved. SERCA2 C674S mutant knock-in (SKI) mice, human AD specimens, and primary ASMCs were subjected to quantitative proteomics, histopathology, and autophagy flux assays. Interventions included Ca2+ chelation (BAPTA-AM), endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyrate, mammalian target of rapamycin (mTOR) inhibitor rapamycin, redox modulator Tempol, calcineurin inhibitor cyclosporine A, peroxisome-proliferator-activated receptor γ (PPARγ) agonist pioglitazone, and SERCA2 agonist [6]-gingerol. Therapeutic efficacy was evaluated in β-aminopropionitrile (BAPN)-induced AD. Human AD specimens and SKI aortas displayed suppressed autophagy within the tunica media. SERCA2 dysfunction activated PI3K-AKT-mTOR signaling pathway, reduced TFEB and Rab7, and impaired autophagosome-lysosome fusion in ASMCs. These defects were rescued by BAPTA-AM, 4-phenylbutyrate, rapamycin, Tempol, or [6]-gingerol, but not by calcineurin or pioglitazone. In vivo, rapamycin and [6]-gingerol restored medial autophagy, suppressed ASMC synthetic phenotype, lowered AD incidence and severity, and preserved medial integrity in BAPN-treated SKI mice. In conclusion, oxidative SERCA2 inactivation evokes cytosolic Ca2+ overload, couples ER/oxidative stress to mTOR hyper-activation, and blunts autophagic flux, thereby establishing a self-amplifying loop that precipitates AD. We define a previously unrecognized SERCA2-Ca2+-mTOR-autophagy axis as a guardian of aortic wall homeostasis and establish autophagy rebalancing and SERCA2 activation as mechanistically grounded therapeutic strategies against AD.

PMID 42509384
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PubMedJPGN reports2026-07-28

Biochemical testing and pathology reveal rare cause of pediatric acute liver failure: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Mosher Tierra L TL, Czepiel Kathryn S KS, Neu Matthew B MB, Fernandez Andrea Carolina Cortes ACC et al.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare metabolic condition that can cause lethargy, ataxia, tachypnea, nausea, vomiting, seizures, coma, and acute liver failure. We present a 26-month-old female with acute liver failure who was diagnosed with HHH 1 week after admission. Histology revealed an acute hepatitic pattern of liver injury with numerous acidophils and glycogenated nuclei without zonal distribution, the former a rarely discussed feature. Acute management included intravenous dextrose and intralipids, with chronic management requiring a protein-restricted diet, glycerol phenylbutyrate for nitrogen scavenging, and citrulline supplementation to support the urea cycle. This case contributes to our growing understanding of the phenotypic presentation of HHH, a rare genetic cause of liver failure not included on newborn screening but with specific treatment implications. We also highlight the importance of collecting biochemical genetics labs and liver biopsy early in the disease course and discuss how a patient's voluntary self-restriction of protein can offer helpful clues in the diagnostic evaluation.

PMID 42516736
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PubMedEpilepsy & behavior : E&B2026-07-17

From synaptic dysfunction to targeted intervention: a comprehensive review of STXBP1 encephalopathy and precision therapeutic strategies.

Samanta Debopam D

STXBP1- related disorders (STXBP1-RD), caused by pathogenic variants in STXBP1 encoding the presynaptic protein MUNC18-1, affects approximately 1 in 30,000-40,000 individuals and is among the most common monogenic developmental and epileptic encephalopathies (DEEs). It is characterized by universal neurodevelopmental impairment, early-onset epilepsy, movement disorders, and autism spectrum features, yet treatment remains largely empirical. We conducted a comprehensive narrative review of studies indexed in PubMed/MEDLINE, Embase, Cochrane Library, ClinicalTrials.gov, and American Epilepsy Society proceedings through January 2026, synthesizing molecularly confirmed cohorts, mechanistic studies, and therapeutic investigations. Over 300 pathogenic variants have been identified, predominantly de novo heterozygous, with haploinsufficiency as the principal mechanism. Seizure onset typically occurs within the first months of life, with the vast majority presenting in the first year. Two broad trajectories emerge across cohorts: spontaneous seizure remission in a substantial minority - most within the first year - and persistent drug-resistant epilepsy in the remainder, with a significant proportion experiencing frequent seizures at long-term follow-up. Severe to profound intellectual disability affects the great majority of individuals; independent ambulation and functional verbal communication are achieved by roughly half and less than one-third, respectively. Movement disorders and autism spectrum features are common, and mortality, while modest in absolute terms, includes a disproportionate contribution from SUDEP. Current management is empirical, with phenobarbital, clobazam, and ketogenic diet supported by the most consistent retrospective cohort evidence for seizure reduction. Emerging precision approaches include AAV-mediated gene replacement, antisense oligonucleotides, 4-phenylbutyrate, CRISPR-based transcriptional activation, microRNA inhibition, and serotonergic modulation. Advances in natural history studies and biomarker development are accelerating mechanism-based therapies, positioning STXBP1-RD as a leading test case for precision medicine in DEEs.

PMID 42462387
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