Drug Database
PH

phenylbutyrate (Luc01 / Luc 01 / Pheburane)

✓ Approved

Duchesnay Inc. · Small Molecule · Small Molecule

What is phenylbutyrate?

phenylbutyrate is a small molecule developed by Duchesnay Inc.. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesLuc01, Luc 01, Pheburane
CompanyDuchesnay Inc.
Drug ClassSmall Molecule
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, Duchesnay Inc.

Therapeutic Indications

phenylbutyrate is developed for 4 unique indications across 1 therapeutic area.

Therapeutic AreaConditionPhase
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

Related Research Articles

PubMedCancer treatment and research communications2026-08-19

A direct comparison of butyrate, 4-phenylbutyrate, and β-hydroxybutyrate in an in vitro tumor therapy model.

Katsika Haralambia H, Purps Daniela D, Montag Christina C, Ludwig Fiona F et al.

Cancer remains the second leading cause of death worldwide, emphasizing the urgent need for more effective therapies. One promising approach is the use of naturally occurring molecules. The short-chain fatty acid butyrate has attracted attention for its protective and anticancer properties in colorectal cancer. However, the beneficial effects of butyrate are restricted to colonocytes. To determine whether systemically available butyrate derivatives could elicit similar effects in other cell types, we investigated 4-phenylbutyrate and β-hydroxybutyrate treatment regimens in a non-colon BALB/c cell line. The anticarcinogenic potential of butyrate derivatives was evaluated using the BALB/c tumor therapy model, which simulates the early stages of malignant cell transformation. Mechanistic effects were investigated through immunoblotting and flow cytometry. Initial results revealed that both butyrate and 4-phenylbutyrate exhibited anticancer effects in a time- and dose-dependent manner. Butyrate and 4-phenylbutyrate promoted histone acetylation, activated the tumor suppressor p53 and the expression of p21, leading to cell cycle arrest, with butyrate inducing a G0/1-phase arrest while 4-phenylbutyrate induced an S-phase arrest. Furthermore, butyrate and 4-phenylbutyrate resulted in reduced caspase-3 activation, while simultaneously increasing the number of apoptotic cells. β-hydroxybutyrate did not show measurable effects in the parameters investigated. In summary, this study provides a new comparative insight into both anticancer effects and the underlying mechanisms of action of the three butyrate derivatives in a non-colon cell model. Our findings indicate that 4-phenylbutyrate represents the more promising derivative in the BALB/c tumor therapy model.

PMID 42617287
Read full article →
PubMedCells2026-08-13

4-Phenylbutyrate Rescue in GABRA1 Variants Associated with Developmental Epileptic Encephalopathies: From Cell and Mouse Models to Humans.

Song Ziang Debbie ZD, Zavalin Kirill K, Shen Wangzhen W, DeLeeuw Melissa B MB et al.

Disease variants in GABR genes encoding γ-aminobutyric acid type A receptor (GABAAR) subunits are major causes of developmental and epileptic encephalopathies (DEEs). There is no effective treatment for these DEEs, although the GABAAR is a major target for antiseizure drugs. We previously identified the therapeutic effect of 4-phenylbutyrate (PBA) in Gabrg2+/Q390X knockin DEE mice and in this study tested the effect of the drug in GABRA1 variants that encode the α1 subunit of GABAAR. We used a multidisciplinary approach including in silico structural modeling, flow cytometry, patch-clamp recordings and biochemistry in conjunction with differential tagging of the wildtype (WT) and the mutant alleles to evaluate the effect of PBA on rescue of GABAAR subunit expression, surface trafficking, and function in vitro in a heterologous HEK293T cell model and in vivo in Gabra1+/A322D mice. We found that the α1 subunit expression at both the total level and the cell surface was reduced when the variant α1 protein was present, suggesting reduced functional receptor availability on the cell membrane and synapse. Patch-clamp recordings identified that α1 variants reduced GABA-evoked current amplitude. In silico prediction indicated reduced protein stability for GABRA1 variants by negative ∆∆G values. PBA increased both total and surface expression of WT α1 and α1 variants and improved expression of both WT and variant α1 alleles when these were co-expressed. Importantly, PBA also increased the GABAAR expression in the cortex and thalamus of the Gabra1+/A322D mice. This study indicates that PBA is a promising treatment option for DEEs associated with GABRA1 mutations. Our previous work has demonstrated that PBA improves proteostasis by enhancing expression of the WT allele, repairing the mutant allele, and reducing endoplasmic reticulum stress in other DEEs associated with GABRG2 and SLC6A1 mutations. Importantly, it can mitigate seizures and improve neurobehavioral phenotypes at behavioral levels. Based on this and our previous work on GABRG2 and SLC6A1 mutations, we propose that PBA holds promise as a common medicine for multiple genetic neurologic disorders that share the proteostasis pathology with a broad clinical application in DEEs.

PMID 42587736
Read full article →
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 ATP-binding cassette subfamily B member 11 (ABCB11) gene. The 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 substitutions. A three-dimensional (3-D) 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. 3-D 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. 3-D 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.NEW & NOTEWORTHY Patients with progressive familial intrahepatic cholestasis type 2 (PFIC2) due to ATP-binding cassette subfamily B member 11 (ABCB11) missense variations may present various phenotypes and exhibit different response patterns to treatments. This study exemplifies this variability and provides an in silico and in vitro framework for characterizing and classifying ABCB11 missense variants. This classification could serve to guide treatment strategies, stratify patients with missense variants in clinical trials, and predict patient outcomes.

PMID 42552878
Read full article →
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
Read full article →
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
Read full article →
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
Read full article →

+1273 more articles available with a free account

Sign up free to view all articles →

Ask about phenylbutyrate