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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

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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PubMedDrug design, development and therapy2026-08-29

Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.

Wei Yutong Y, Wang Jie J, Ji Yanan Y, Shang Tongxin T et al.

Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all" approach toward "precisely stratified" medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.

PMID 42666355
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PubMedGenes2026-08-27

4-Phenylbutyrate Plus Wildtype GAT-1 Augmentation: A Dual Therapy to Rescue SLC6A1 Variant-Associated Developmental and Epileptic Encephalopathy.

Delahanty Aiden James AJ, James Kaitlin K, Carter Emma Grace EG, Song Ziang Debbie ZD et al.

Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. We report a novel de novo missense mutation p.Ala305Val in GAT-1 encoding SLC6A1, in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. Ala305Val was compared with the residue-matched comparator p.Ala305Thr (Ala305Thr). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. AI-based stability predictors uniformly indicated destabilization of GAT-1 p.Ala305Val and GAT-1 p.Ala305Thr. GAT-1 p.Ala305Val reduced 3H GABA uptake across HEK293Ts, astrocytes, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ~80% in GAT-1 p.Ala305Val; PBA reduced ER retention to approximately ~40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved GABA uptake in the heterozygous condition but combined PBA plus wildtype allele augmentation produced rescue greater than either intervention alone in the available dose-response ranges. GAT-1 p.Ala305Val is a trafficking-impaired, loss-of-function variant whose dysfunction is amenable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter expression. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by genetic approaches.

PMID 42650175
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PubMedInternational journal of molecular sciences2026-08-27

TUDCA and 4-PBA in Preclinical Models of Beta-Cell Secretory Failure: A Systematic Review and Bayesian Meta-Analysis.

Ramos-Jiménez Arnulfo A, Rubio-Valles Mariazel M, Guereca-Arvizuo Jaime J, Ramos-Hernández Javier A JA et al.

The progressive failure of pancreatic beta-cells under chronic glucolipotoxicity drives the pathogenesis of type 2 diabetes mellitus (T2DM). This metabolic stress overwhelms the folding capacity of the endoplasmic reticulum (ER), hyperactivates the unfolded protein response (UPR), engages terminal pro-apoptotic signaling through C/EBP-homologous protein (CHOP), and promotes beta-cell dedifferentiation. In this systematic review and meta-analysis, registered with PROSPERO (CRD420261370436), we evaluated the preclinical efficacy of the low-molecular-weight chemical chaperones tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) in preserving beta-cell exocytotic identity and mitigating ER stress. Following PRISMA 2020 guidelines, a systematic search of PubMed, Scopus, and Web of Science (January 2016-May 2026) identified four eligible experimental studies. Preclinical models (INS-1 and βTC-6 cell lines, Wistar rats, and C57BL/6 mice) exposed to a high-fat diet (HFD), a high-fat/high-fructose diet (HFHFD), cholesterol loading, or protein restriction followed by high-fat feeding showed impaired or dysregulated glucose-stimulated insulin secretion (GSIS) and upregulated ER-stress markers. Co-administration of TUDCA or 4-PBA moved secretory output toward the healthy-control phenotype in every model and reduced pro-apoptotic markers in the three models in which they were measured. A hierarchical Bayesian random-effects meta-analysis of the between-arm GSIS restoration ratio at stimulatory glucose yielded a pooled ratio of 1.85 (95% credible interval [CrI] 1.38 to 2.43), with the entire credible mass above the null (posterior probability of benefit 0.996). This estimate was stable across nine prior specifications for the between-study standard deviation and in every leave-one-out analysis, including exclusion of the single hypersecretion model (1.98, 95% CrI 1.09 to 3.18). Between-study variance was small but weakly identified from only four studies and is reported as exploratory. Pooling instead on the registered within-arm stimulation-index scale, a change in metric declared as a protocol deviation, gave 1.46 (95% CrI 0.73 to 2.58) with substantial heterogeneity (I2 = 89.3%), so the evidence supports restoration of absolute glucose-stimulated insulin output rather than of fold glucose responsiveness. Because no source report documents blinding of outcome assessment, the pooled estimate should be read as an upper bound. In conclusion, TUDCA and 4-PBA act as chemical chaperones that alleviate ER stress and may prevent terminal UPR activation and preserve the beta-cell exocytotic machinery, positioning them as candidate disease-modifying agents that merit confirmatory clinical evaluation.

PMID 42653271
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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
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