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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

PubMedCell calcium2026-09-29

SERCA2b loss of function drives pigmentation by inducing adaptive ER stress and enhancing mitochondrial calcium uptake: significance in pathological hyperpigmentation associated with Darier's Disease.

Sharma Akshay A, Saurav Suman S, Sharma Preity P, Pandhi Deepika D et al.

Pigmentation is a critical protective mechanism that safeguards the skin against UV-induced damage, whereas dysregulated pigmentation predisposes to pigmentary disorders and skin malignancies. Although calcium signaling has emerged as an important regulator of melanogenesis, the identity of the calcium-handling proteins and the molecular mechanisms linking calcium dynamics to pigmentation remain poorly understood. Here, we identify the ER calcium pump SERCA2b as a negative regulator of pigmentation through modulation of ER stress and mitochondrial calcium uptake. We demonstrate that SERCA2b expression inversely correlates with pigmentation levels, and gain- and loss-of-function studies establish SERCA2b as a suppressor of melanogenesis. Mechanistically, SERCA2b depletion induces adaptive ER stress, enhances ER-mitochondrial proximity, and promotes mitochondrial calcium uptake. Notably, mutations in SERCA2b are associated with Darier disease, a condition characterized by hyperpigmented skin lesions, although the underlying mechanism remains unknown. To address this, we generated SERCA2b mutants corresponding to variants identified in Indian Darier's disease patients and examined their effects on pigmentation, ER stress, and mitochondrial calcium dynamics. The mutant phenotypes closely recapitulated SERCA2b loss-of-function effects, demonstrating that adaptive ER stress and enhanced mitochondrial calcium signaling underlie hyperpigmentation associated with Darier's disease. Importantly, treatment with 4-phenylbutyrate (4-PBA), an FDA-approved ER stress alleviator, rescued mutant-induced hyperpigmentation, reduced ER stress, and normalized mitochondrial calcium uptake. Collectively, our findings uncover a previously unrecognized role of SERCA2b in skin pigmentation, establish a mechanistic link between SERCA2b mutations and hyperpigmentation; and identify adaptive ER stress pathways as potential therapeutic target for pigmentary disorders.

PMID 42810200
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PubMedPediatric neurology2026-09-21

Glycerol Phenylbutyrate Treatment in a Pediatric Cohort of SLC6A1-Related Neurodevelopmental Disorder.

Díaz-Gómez Asunción A, Ballesteros-Cogollos Virgínia V, Calvo-Medina Rocío R, Aznar-Laín Gemma G et al.

The SLC6A1 gene encodes the gamma-aminobutyric acid transporter 1 protein, which facilitates the reuptake of gamma-aminobutyric acid from the synaptic cleft in inhibitory synapses back into presynaptic neurons and glial cells. SLC6A1 haploinsufficiency leads to neurodevelopmental impairment including epilepsy, movement disorders, intellectual disability, and autism spectrum disorder. SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is a rare condition with autosomal dominant inheritance for which there is no cure. Acting as a chemical chaperone, glycerol phenylbutyrate, used for urea cycle disorders, can cross the blood-brain barrier and increase GABA transporter 1 surface cell expression in animal and in vitro models. This research aimed to review the clinical characteristics of a cohort of pediatric patients with SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) in Spain and to assess the efficacy and safety of glycerol phenylbutyrate treatment. We have conducted retrospective review of the clinical characteristics of SLC6A1-NDD pediatric patients from 13 hospitals in Spain and investigated the efficacy and safety of glycerol phenylbutyrate treatment. Fourteen patients were included in the cohort, out of which eleven were treated with glycerol phenylbutyrate. A significant reduction in the number of epileptic seizures was observed in 80% of patients with uncontrolled seizures at baseline and 40% became seizure-free. A clear improvement in video-electroencephalogram abnormalities was evident in 64%, while 27.2% experienced cognitive improvement and 36.3% showed significantly improved psychiatric manifestations. Seven of the eleven treated patients experienced some side effects from which three has discontinued the treatment. Glycerol phenylbutyrate treatment is relatively well tolerated, and although it is effective in reducing the frequency of seizures and improving video-electroencephalogram abnormalities, it is less effective in ameliorating cognitive and psychiatric manifestations.

PMID 42767125
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PubMedMolecular genetics and metabolism2026-09-15

Drug repurposing of glycerol phenylbutyrate for children with SLC6A1-related neurodevelopmental disorder: A prospective open-label case series.

van Walree E S ES, Dekker D Z DZ, Sprengers J J JJ, Boussaad I I et al.

SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is characterized by intellectual disability, epilepsy, and behavioral difficulties. It is caused by pathogenic variants in SLC6A1, encoding the GABA transporter protein 1 (GAT1). Glycerol phenylbutyrate increases GAT1 expression in preclinical models and has shown promising effects on seizure control in a clinical study. We conducted a prospective open-label observational study of glycerol phenylbutyrate (target dose 11.2 ml/m2/day) in pediatric patients with NDD and/or epilepsy and rare SLC6A1 variants (including (likely) pathogenic variants and variants of uncertain significance (VUS)). Primary outcomes were personalized goals. Secondary outcomes included seizure burden, development, irritability, quality of life, and tolerability. We initiated treatment in six children; one was excluded due to lack of consent, leaving five for analysis. Three had (likely) pathogenic SLC6A1 variants and constituted the main case series; two had a VUS and were analyzed separately. Mean treatment duration was 33.7 months (range 16-46). Side effects included mild gastrointestinal complaints (n = 2) and a honey-like body odor (n = 3). All three molecularly confirmed SLC6A1-NDD patients achieved or exceeded predefined personalized goals at 12 months, with improvements in goals associated with amelioration in behavior and development, even though standardized developmental assessments show a more nuanced picture. In a single patient with absence-like episodes without clear EEG correlate at baseline, a reduction in these events and in epileptiform activity on EEG was observed following treatment. Positive signals in quality of life (n = 1) and irritability (n = 2) questionnaires were observed. Glycerol phenylbutyrate was associated with improvements in individualized outcomes in children with SLC6A1-NDD. However, personalized goal attainment measures are susceptible to expectation and observer bias in open-label study designs. Controlled studies are needed to determine efficacy and guide patient selection.

PMID 42735473
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PubMedJournal of child neurology2026-09-13

Phenylbutyrate-Responsive SLC6A1-Related Neurodevelopmental Disorder Associated With a Familial Variant.

Ghawi Odette El OE, Beemarajan Eniya E, Samanta Debopam D, Ramani Praveen Kumar PK

SLC6A1-related neurodevelopmental disorder is a synaptopathy characterized by developmental delay, epilepsy, and neurobehavioral manifestations with marked phenotypic variability. Variants impair γ-aminobutyric acid (GABA) transporter-1 (GAT-1) folding and trafficking, reducing inhibitory neurotransmission and promoting hyperexcitability. Pharmacologic chaperones such as 4-phenylbutyrate (4-PBA) may restore GAT-1 function. We report a 3-generation family harboring a heterozygous SLC6A1 variant with segregating neurodevelopmental and epileptic phenotypes. The proband presented with drug-resistant developmental and epileptic encephalopathy, multiple seizure types, diffuse epileptiform abnormalities, and global developmental delay. Segregation analysis demonstrated co-segregation of the variant with epilepsy and neurodevelopmental features across affected relatives. Because of persistent seizures despite antiseizure medications, glycerol phenylbutyrate (GPB), a prodrug of 4-PBA, was initiated, resulting in complete seizure freedom and reduction of epileptiform discharges on follow-up electroencephalography. These findings highlight the potential role of genotype-informed precision therapy in SLC6A1-related disorders and underscore the importance of careful variant interpretation in familial cases.

PMID 42731082
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PubMedThe Lancet. Neurology2026-09-09

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

Cudkowicz Merit E ME, Shefner Jeremy J, van den Berg Leonard H LH, Chio Adriano A et al.

RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. Sanofi.

PMID 42716044
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PubMedBioorganic chemistry2026-08-30

Repurposing butoconazole as a GRP78 substrate-binding domain (SBD) inhibitor to induce endoplasmic reticulum stress-mediated apoptosis in triple-negative breast cancer.

Song Yaowen Y, Yuan Ziyue Z, Li Zhijia Z, Huang Yunli Y et al.

Triple-negative breast cancer (TNBC) is aggressive with limited therapies and poor prognosis. Butoconazole, a clinical topical imidazole antifungal for vulvovaginal candidiasis, has not previously been investigated for TNBC treatment. Here, we repurposed butoconazole as a novel allosteric inhibitor of glucose-regulated protein 78 (GRP78) for TNBC treatment. It suppressed TNBC cell proliferation (IC50: 13.61 ± 1.07 μM for MDA-MB-231, 26.17 ± 1.17 μM for MDA-MB-468), inhibited migration, and induced apoptosis, resulting in 68.28% tumor growth inhibition in MDA-MB-231 xenograft mouse models without evident toxicity. Mechanistically, we combined RNA-seq and limited proteolysis-mass spectrometry (LiP-MS) to identify GRP78 as its potential target, validated by surface plasmon resonance (SPR), biolayer interferometry (BLI), cellular thermal shift assay (CETSA), drug-affinity-responsive target-stability (DARTS) assay and molecular dynamics simulations. Unlike existing GRP78 modulators, butoconazole allosterically attaches to the helical bundle at the distal tip of GRP78 substrate-binding domain α (SBD-α), rearranges its binding pocket and blocks GRP78 chaperone activity. This triggers endoplasmic reticulum (ER) stress, elevates the expression levels of ATF4 and CHOP and induces apoptosis. Rescue assays with 4-phenylbutyrate (4-PBA), ATF4/CHOP knockdown or GRP78 overexpression attenuated butoconazole's anti-tumor activity. Collectively, butoconazole suppresses TNBC through allosteric GRP78 inhibition to trigger ER stress-mediated ATF4/CHOP apoptosis, and represents a promising lead compound for further development as a systemic anti-TNBC agent through formulation optimization.

PMID 42669273
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