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valproate semisodium (Depakote ER / divalproex ER)

✓ Approved

AbbVie, Inc. · SCN1A · Small Molecule

What is valproate semisodium?

valproate semisodium is a small molecule developed by AbbVie, Inc.. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesDepakote ER, divalproex ER
CompanyAbbVie, Inc.
Drug ClassSmall Molecule
Molecular TargetSCN1A, SCN2A, SCN3A
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, AbbVie, Inc.

Mechanism of Action

Molecular Targets

valproate semisodium acts on 3 molecular targets:

SCN1Asodium voltage-gated channel alpha subunit 1 (DEE6B, FEB3)
SCN2Asodium voltage-gated channel alpha subunit 2 (Na(v)1.2, BFNIS)
SCN3Asodium voltage-gated channel alpha subunit 3 (Nav1.3, NAC3)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

valproate semisodium is developed for 3 unique indications across 3 therapeutic areas.

Therapeutic AreaConditionPhase
Nervous system disordersGeneralised tonic-clonic seizure✓ Approved
Psychiatric disordersBipolar disorder✓ Approved
Surgical and medical proceduresMigraine prophylaxis✓ Approved

Related Research Articles

PubMedMolecular and cellular neurosciences2026-08-30

Reframing neuropsychiatric disorders: Nuclear calcium signaling as a core signaling axis of mitochondrial proteostasis and synaptic energy homeostasis.

Mohan Maneesh M, Mannan Ashi A, Mondal Debasmita D, Chabara Charu C et al.

Neuropsychiatric disorders have a high global health impact; however, the molecular basis of these disorders is still not fully understood due to the intricate complexity of neuronal homeostasis. In this review article, we have highlighted an emerging paradigm that places nuclear calcium signaling at the apex of cellular metabolism by bridging synaptic functions and mitochondrial proteostasis. We have highlighted how cytosolic and nucleoplasmic Ca2+ transients orchestrate a "transcription-to-translation" process that is crucial for the expression of mitochondrial proteasomal and biogenesis-related genes. In this review article, we have critically analyzed pathways, including ER-IP3R coupling, MCU-mediated Ca2+ uptake, and the PINK1-Parkin pathway, that contribute to a "synaptic energy gap" due to bioenergetic failure and oxidative stress arising from aberrant calcium homeostasis. One of the major highlights of this review article is our critical examination of the CaMKII-CREB-BDNF pathway, which plays a crucial role in mitochondrial biogenesis in response to alterations in energy homeostasis. We have explored beyond the conventional by critically analyzing how modern psychotropic agents such as Ketamine, Lithium, and Valproate effectively reboot these pathways to overcome bioenergetic failure. Through the integration of the latest advances in structural biology with clinical psychiatry, this review creates a framework where mitochondrial pathology is not only a consequence, but rather a cause, of psychiatric disorders. Ultimately, this review creates a framework for developing next-generation, molecularly targeted therapeutics capable of healing the energetic defects that underlie the human mind.

PMID 42669372
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PubMedClinical and experimental pharmacology & physiology2026-08-30

ANGII Initiated HSF2 Trans-Activating HIF-1α Through Induction of ER Stress to Promote Cardiac Hypertrophy.

Cao Renchuang R, Meng Qingying Q, Li Gengyuan G, Yuan Shumei S et al.

Heat shock factor 2 (HSF2) and hypoxia-inducible factor 1α are activated by angiotensin II (ANGII) in cardiomyocytes. The endoplasmic reticulum (ER) stress plays a critical role in cardiac hypertrophy. Moreover, HIF-1α is known to be regulated by HSF2 in tumour cells. In this study, we hypothesised and clarified whether HSF2 trans-activated HIF-1α through initiation of ER stress in hypertrophic cardiomyocytes. Myocardial hypertrophy was induced by the treatment of ANGII. Expression of the gene or protein was assessed by applying RT-PCR, WB, ICC and IHC. Luciferase and CHIP were applied to detect the transcription of HIF-1α by HSF2. Both in vitro and in vivo, the expression of HIF-1α, ER stress markers and HSF2 was increased in ANGII-treated hypertrophic cardiomyocytes. Blocking ER stress suppressed the expression of HSF2 and HIF-1α in ANGII-treated cardiomyocytes. Silencing HSF2 inhibited HIF-1α, thereby reducing hypertrophy but had no effect on ER stress. Similarly, silencing HIF-1α reduced hypertrophy without affecting ER stress or HSF2 expression. HSF2 transcriptionally activated HIF-1α. We concluded that ER stress induced by ANGII activates HSF2, which then trans-activates HIF-1α, promoting cardiac hypertrophy.

PMID 42669620
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PubMedNPJ breast cancer2026-08-30

Genomic characterization of ER-positive primary tumors and corresponding relapses identifies potentially targetable alterations.

Schagerholm Stanev Caroline C, Robertson Stephanie S, Toosi Hosein H, Sifakis Emmanouil G EG et al.

The majority of breast cancer patients have tumors expressing estrogen receptor α (ER) and receive endocrine therapy. However, around one-third relapse in their disease, predominantly with retained ER expression. Molecular alterations are proposed to be contributors to the resistance mechanisms. Patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer with an ER-positive relapse < 5 years of ongoing endocrine therapy were retrospectively assessed. Extracted DNA was analyzed through panel sequencing, and RNA by microarray, from patients' primary (n = 58), and paired relapse tumors (n = 54), and tumor-free lymph nodes (DNA germline controls, n = 62). Several single-nucleotide variations and copy number variations showed nominal exploratory associations with worse overall survival. Copy number correlations with intrinsic subtypes and individual gene expression supported the findings. These results identify hypothesis-generating genomic and transcriptomic features, including potentially targetable alterations, in a clinically defined cohort of endocrine-resistant breast cancer patients.

PMID 42668305
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PubMedBiochemistry. Biokhimiia2026-08-30

Dynamics of Aspartate Isomerization and Its Cellular Implications: Evidence for Isoaspartate Formation in ER-Folded Proteins and Stress-Responsive Regulation of PCMT1.

Biterge Burcu B

Spontaneous isomerization of aspartate and deamidation of asparagine residues into isoaspartate (isoAsp) constitute major non-enzymatic post-translational modifications that alter protein structure, stability, and turnover. The repair enzyme protein L-isoaspartate O-methyltransferase (PCMT1) catalyzes methylation of isoAsp residues, thereby preventing their accumulation and preserving proteome integrity. Although PCMT1 has been studied extensively in cytoplasm and nucleus, its relationship to endoplasmic reticulum (ER) proteostasis remains poorly understood. Here, we investigated dynamics of aspartate isomerization within the cell, focusing on isoAsp accumulation and the regulation of PCMT1 localization under physiological and stress conditions. Using immunofluorescence, subcellular fractionation, and in vitro methylation assays, we detected isoAsp-modified proteins within the ER-enriched fractions of HeLa cells. We found that ER stress induction enhanced formation of isoAsp-containing proteins, with MG132 treatment producing the highest accumulation. PCMT1 expression increased under both stress conditions, accompanied by distinct subcellular redistribution between the cytoplasmic and nuclear compartments. These observations indicate that ER-folded proteins are susceptible to spontaneous aspartate isomerization, and that PCMT1 activity dynamically responds to proteostatic stress. Our findings provide the first experimental evidence linking isoAsp formation within the ER to PCMT1-mediated protein repair, thereby integrating chemical instability with cellular quality-control pathways. This study establishes a structural and cellular framework for understanding the dynamics of aspartate isomerization in the cell and underscores significance of PCMT1 in maintaining proteostasis under stress conditions.

PMID 42669562
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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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PubMedBiochemistry. Biokhimiia2026-08-30

Effect of Cu2+ on the Nucleoli of Cultured Astrocytes from the Rat Cerebral Cortex.

Genrikhs Elizaveta E EE, Stelmashook Elena V EV, Smirnova Elena A EA, Golyshev Sergey A SA et al.

Cultured astrocytes were incubated with CuCl2, which caused dose-dependent cell death (25-200 μM, 24 h). Immunocytochemical detection of the nucleolar protein nucleophosmin/B23 (NPM/B23) demonstrated that exposure to Cu2+ (100 μM, 24 h) caused a significant increase in the surface area of NPM/B23 clusters, which was accompanied by the changes in the nucleolar ultrastructure characteristic of nucleolar stress. Longer incubation of astrocytes with Cu2+ (100 μM, 48 h) led to accumulation of the endoplasmic reticulum (ER) stress marker GRP78, which was accompanied by the increase in nucleolar size and migration of the nucleolar material into the nucleoplasm.

PMID 42669563
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