Kinenza (enzastaurin) / Denovo, Aytu BioPharma - LARVOL DELTA

PRKCB Mediates Ferroptosis-Immune Crosstalk in Acute Lung Injury: Insights from Integrated Single-Cell Transcriptomics. (PubMed, J Inflamm Res) - "Key predictions were validated in an LPS-induced alveolar epithelial cell (MLE-12) model using the PRKCB inhibitor Enzastaurin and the ferroptosis inhibitor Ferrostatin-1...Our study provides the first single-cell resolution map of ferroptosis heterogeneity in ALI, uncovering a PRKCB-mediated positive feedback loop between ferroptosis and immune dysregulation. These findings identify PRKCB as a potential therapeutic target to disrupt this pathogenic crosstalk."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Critical care • Inflammation • Pulmonary Disease • Respiratory Diseases • ACSL4 • GPX4 • PRKCB • PRKCH • SLC7A11

Protective Effect of the NHE1 Inhibitor Buthutin A on Oxidative Stress-Induced Apoptosis in HUVECs. (PubMed, ACS Omega) - "We further found that the calcium chelator (BAPTA-AM), Na+/Ca2+-exchanger (NCX) inhibitor (SN6), cPKC inhibitor (Go6976), and PKCβ inhibitor (LY317615) had no effect on the protective effect of Buth A in HUVECs, including the inhibition of oxidative stress and apoptosis. Further results indicated that Buth A alleviated oxidative stress and apoptosis caused by myocardial hypertrophy via NHE1 inhibition in AngII-induced mice. Buth A reduced oxidative stress-induced apoptosis and exerted protective effects against AngII-induced cardiac injury in vivo and in vitro via NHE1 inhibition, which might be associated with [Ca2+]c and PKCβ activities."

IO biomarker • Journal • Cardiovascular • BAX • BCL2 • PRKCB

Precision Targeting of PI3K/mTOR in Diffuse Midline Glioma: GCT007 as a Novel Brain-Penetrant PIK3CA Inhibitor (ISPNO 2026) - P1 | "However, in Phase I studies (NCT01547546), the systemic pan-PI3K inhibitor, paxalisib, induces adverse events in patients (e.g., hyperglycemia), undermining treatment efficacy...Phosphoproteomic profiling following PI3K/AKT/mTOR inhibition showed activated calcium-dependent PKC signaling, therefore, we tested GCT-007 in combination with the brain-penetrant PKC inhibitors: enzastaurin, and JLD14 (novel therapy in development in our laboratory) and with immune checkpoint inhibitor anti-PD1 therapies...Together these findings define a precision treatment strategy which targets DMG genetic dependencies, circumvents therapeutic resistance and primes the tumor for immune engagement. Ongoing spatial profiling of the tumor immune microenvironment and organ-toxicity is underway to support translation."

IO biomarker • Brain Cancer • Diabetes • Diffuse Midline Glioma • Gastroenterology • Gastrointestinal Disorder • Glioma • Immunology • Mucositis • Solid Tumor • PIK3CA • PIK3CD • PIK3CG

High-throughput screening of small molecule Wnt/β-catenin activators for hair and nail growth. (PubMed, Commun Biol) - "Nine compounds significantly activated Wnt signaling, including antivirals (imidocarb, proflavine, aminoacridine), anticancer agents (entinostat, enzastaurin, abemaciclib), and GSK-3β inhibitors (BIO, CP21R7). In mice, aminoacridine-especially combined with minoxidil-showed the strongest hair regrowth, while proflavine and imidocarb enhanced nail elongation. These results reveal new therapeutic candidates for hair and nail regeneration."

Journal • Oncology • RSPO3 • WIF1

Lost in translation: Do preclinical studies predict clinical failure in GBM? (SNO 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (SNO 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (WFNOS 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Oncology • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (WFNOS 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor

Challenges in comparing outcomes of frontline clinical trials for diffuse large B-cell lymphoma patients selected based on the international prognostic index: A real-world analysis from the danish lymphoma registry (ASH 2025) - P3 | "This study aimed to present real-world outcomes among patients treated with R-CHOP/R-CHOP-like (+/-etoposide) regimens who met the inclusion criteria for four currently ongoing phase 3 trials: GOLSEEK-1(NCT06356129, R-CHOP+golcadomide vs. R-CHOP+placebo), SKYGLO (NCT06047080,glofitamab+polatuzumab+R-CHP vs. polatuzumab-R-CHP), ENGINE-1 (NCT03263026, enzastaurine+R-CHOP vs. R-CHOP), and ZUMA-23 (NCT05605899, axi-cel vs. standard of care 1st line therapy). This retrospective analysis of 3,475 newly diagnosed DLBCL patients assessed real-worldoutcomes and the impact of trial eligibility criteria across four ongoing frontline trials. Variations in IPIthresholds and clinical/laboratory requirements resulted in substantial differences in the proportion oftrial-eligible patients. Among the analyzed trials, ZUMA-23 had the most stringent eligibility criteria,resulting in the lowest eligibility rate and the exclusion of many younger individuals."

Clinical • Real-world • Real-world evidence • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Human Immunodeficiency Virus • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma

Exploiting Cell-of-Origin Vulnerabilities to Guide Multimodal Strategies in Diffuse Midline Glioma (WFNOS 2025) - "To mitigate this, we developed multimodal strategies that combined clinically relevant PI3K/mTOR inhibitors (paxalisib, GCT-007, everolimus) with the antihyperglycemic agent metformin, which restored glucose homeostasis, suppressed insulin receptor activity, and extended survival in DMG xenograft models. Phosphoproteomic profiling identified therapy-induced activation of calcium-dependent PKC signaling, prompting combination with the brain-penetrant PKC inhibitor enzastaurin, further extending survival...Together, our findings define a multimodal, precision treatment strategy that targets core DMG genetic dependencies, rewires tumor cell identity, circumvents systemic resistance, and primes an immunologically “cold” tumor for immune engagement and clinical translation. We are currently designing an early-phase clinical trial that incorporates sequential small-molecule therapies and ICIs delivered via focused ultrasound, aiming to provide patients with a meaningful and..."

IO biomarker • Brain Cancer • CNS Disorders • Diabetes • Diffuse Midline Glioma • Glioma • Multiple Sclerosis • Solid Tumor • CD8 • H3-3A • HLA-DRA • IR • PD-L1 • PIK3CA

Exploiting Cell-of-Origin Vulnerabilities to Guide Multimodal Strategies in Diffuse Midline Glioma (SNO 2025) - "To mitigate this, we developed multimodal strategies that combined clinically relevant PI3K/mTOR inhibitors (paxalisib, GCT-007, everolimus) with the antihyperglycemic agent metformin, which restored glucose homeostasis, suppressed insulin receptor activity, and extended survival in DMG xenograft models. Phosphoproteomic profiling identified therapy-induced activation of calcium-dependent PKC signaling, prompting combination with the brain-penetrant PKC inhibitor enzastaurin, further extending survival...Together, our findings define a multimodal, precision treatment strategy that targets core DMG genetic dependencies, rewires tumor cell identity, circumvents systemic resistance, and primes an immunologically "cold" tumor for immune engagement and clinical translation. We are currently designing an early-phase clinical trial that incorporates sequential small-molecule therapies and ICIs delivered via focused ultrasound, aiming to provide patients with a..."

IO biomarker • Brain Cancer • CNS Disorders • Diabetes • Diffuse Midline Glioma • Glioma • Multiple Sclerosis • Solid Tumor • CD8 • H3-3A • HLA-DRA • IR • PD-L1 • PIK3CA

MARCKS effector domain phosphorylation state as a regulator of tunneling nanotubes in glioblastoma and normal human astrocyte biology (SNO 2025) - "Pharmacological modulation of PKC with phorbol ester agonist (PMA) or inhibitor (Enzastaurin), and treatment with a MARCKS ED peptide (MED2), assessed effects on TNTs. Doxycycline-inducible U87 MARCKS ED mutants (WT, pseudo-phosphorylated [PP], non-phosphorylatable [NP]) were used to dissect MARCKS phosphorylation roles... JX14 co-cultured with NHAs exhibited increased temozolomide resistance... MARCKS ED phosphorylation via PKC promotes functional TNT formation and mitochondrial trafficking between GBM cells and astrocytes, contributing to chemoresistance. Targeting MARCKS or PKC may represent a novel strategy to disrupt TNT-mediated resistance mechanisms in GBM."

Brain Cancer • Glioblastoma • Solid Tumor • ACTG1 • MARCKS • PTEN

Identification of ferroptosis- and mitochondrial metabolism-related biomarkers and the potential molecular mechanisms of poor ovarian response. (PubMed, J Ovarian Res) - "PLA2G4B and PRKCG have been identified as potential mitochondrial- and ferroptosis-related biomarkers in POR, providing valuable insights for exploring the pathogenesis of POR. These findings may also aid in the development of new diagnostic and therapeutic strategies for POR."

Biomarker • Journal

MARCKS effector domain phosphorylation state as a regulator of tunneling nanotubes in glioblastoma and normal human astrocyte biology (WFNOS 2025) - "Pharmacological modulation of PKC with phorbol ester agonist (PMA) or inhibitor (Enzastaurin), and treatment with a MARCKS ED peptide (MED2), assessed effects on TNTs. Doxycycline-inducible U87 MARCKS ED mutants (WT, pseudo-phosphorylated [PP], non-phosphorylatable [NP]) were used to dissect MARCKS phosphorylation roles... JX14 co-cultured with NHAs exhibited increased temozolomide resistance... MARCKS ED phosphorylation via PKC promotes functional TNT formation and mitochondrial trafficking between GBM cells and astrocytes, contributing to chemoresistance. Targeting MARCKS or PKC may represent a novel strategy to disrupt TNT-mediated resistance mechanisms in GBM."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ACTG1 • MARCKS • PTEN

Exploiting Cell-of-Origin Vulnerabilities to Guide Multimodal Strategies in Diffuse Midline Glioma (WFNOS 2025) - "To mitigate this, we developed multimodal strategies that combined clinically relevant PI3K/mTOR inhibitors (paxalisib, GCT-007, everolimus) with the antihyperglycemic agent metformin, which restored glucose homeostasis, suppressed insulin receptor activity, and extended survival in DMG xenograft models. Phosphoproteomic profiling identified therapy-induced activation of calcium-dependent PKC signaling, prompting combination with the brain-penetrant PKC inhibitor enzastaurin, further extending survival...Together, our findings define a multimodal, precision treatment strategy that targets core DMG genetic dependencies, rewires tumor cell identity, circumvents systemic resistance, and primes an immunologically "cold" tumor for immune engagement and clinical translation. We are currently designing an early-phase clinical trial that incorporates sequential small-molecule therapies and ICIs delivered via focused ultrasound, aiming to provide patients with a..."

IO biomarker • Brain Cancer • CNS Disorders • Diabetes • Diffuse Midline Glioma • Glioma • Multiple Sclerosis • Solid Tumor • CD8 • H3-3A • HLA-DRA • IR • PD-L1 • PIK3CA

Leveraging Medulloblastoma Clonal Dynamics to Overcome Treatment Resistance. (PubMed, Clin Cancer Res) - "This work provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • BMI1 • PLK1

An MHC-Related Gene's Signature Predicts Prognosis and Immune Microenvironment Infiltration in Glioblastoma. (PubMed, Int J Mol Sci) - "We further propose I-BET-762 and Enzastaurin as potential therapeutic candidates for glioma. In conclusion, the four-gene signature we identified and the corresponding risk score model constructed from it provide valuable tools for the prognosis prediction of glioblastoma multiforme (GBM) and may guide personalized treatment strategies. The least absolute shrinkage and selection operator (LASSO) risk score has demonstrated significant prognostic evaluation utility in clinical GBM patients, bringing potential implications for patient stratification and the optimization of treatment regimens."

Biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • FCGR2B • MXRA5 • TNFRSF9 • TNFSF14

Prophylactic Enzastaurin Treatment Reduced Right Ventricular Fibrosis and Alleviated Right Ventricular Dysfunction in a Mouse Model of Pressure-overloaded RV Failure (ATS 2025) - "Since therapeutic Enzastaurin was administered at a time when cardiac Snail expression peaked in the pulmonary artery banding (PAB) model, one week after PAB, we hypothesized that preventing cardiac Snail expression by prophylactic Enzastaurin, administered prior to PAB, was required to reduce RV fibrosis and improve RV function in the pressure-overloaded RV. Eighteen-week-old male and female Myh6 (myosin heavy chain 6)MerCreMer-mTmG mice received a single intraperitoneal injection of tamoxifen (0.025mg/100μl), 2 weeks prior to the administration of Enzastaurin (5mg/kg/day; Selleck Chemical LLC, TX) or vehicle control via a subcutaneous Alzet mini-osmotic pump (200μl reservoir; delivery rate, 0.15μl/hour; Cupertino, CA) for 6 weeks. Unlike therapeutic Enzastaurin, prophylactic Enzastaurin substantially reduced PAB-induced RV fibrosis, and was associated with improvements in RV EF. These data support a role of Enzastaurin-mediated Snail inhibition as a promising..."

Preclinical • Cardiovascular • Fibrosis • Heart Failure • Immunology • Pulmonary Arterial Hypertension • Respiratory Diseases • SNAI1 • TGFB1

Determining the biomarkers and pathogenesis of myocardial infarction combined with ankylosing spondylitis via a systems biology approach. (PubMed, Front Med) - "Enzastaurin, meglitinide, and nifedipine were predicted as potential therapeutic agents. Our study indicates that S100A12 and MCEMP1 exhibit significant potential as biomarkers and therapeutic targets for AS-MI, offering novel insights into the underlying etiology of this condition."

Biomarker • Journal • Ankylosing Spondylitis • Cardiovascular • Immunology • Inflammation • Inflammatory Arthritis • Myocardial Infarction • Rheumatology • Seronegative Spondyloarthropathies • S100A12

Targeting PKC as a Therapeutic Strategy to Overcome Chemoresistance in TNBC by Restoring Aurora Kinase B Expression. (PubMed, J Cell Mol Med) - "By taking advantage of a library screening with various kinase inhibitors, we found that the small-molecule inhibitor enzastaurin targeting protein kinase C (PKC) could overcome resistance in TNBC cells. Moreover, the efficiency of dual treatment was largely determined by AURKB, implying that AURKB could be a potential predictive marker for stratifying patients who may benefit from the combinatorial treatment. Collectively, our study not only unravels a novel underlying mechanism for paclitaxel resistance in TNBC but also provides a new potential combinatorial therapeutic strategy in the clinic."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKB

Overcoming aminoglycoside antibiotic resistance in Mycobacterium tuberculosis by targeting Eis protein. (PubMed, In Silico Pharmacol) - "Based on the three-level screening and Molecular Mechanics generalized Born surface area (MM/GBSA) scores, five drugs including Isavuconazonium sulfate, Cefotiam Hexetil Hydrochloride, Enzastaurin (LY317615), Salbutamol sulfate (Albuterol), and Osimertinib (AZD9291) were considered as potential Eis inhibitors. The PCA and FEL analysis also confirmed the structural stability of the complexes. Overall, these drugs displayed promising results as Eis inhibitors, that can be regarded as suitable candidates for experimental validation."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Integrating traditional QSAR and read-across-based regression models for predicting potential anti-leishmanial azole compounds. (PubMed, Mol Divers) - "Furthermore, the pIC50 values of an accurate external set of 2000 azole compounds from the ZINC20 database were simultaneously predicted by CM2 + SVR + Boosting models and docked against the LdGlyRS, which identified Bazedoxifene, Talmetacin, Pyrvinium, Enzastaurin as leading FDA candidates, whereas three novel compounds with the database code ZINC000001153734, ZINC000011934652, and ZINC000009942262 displayed stable docked interactions and favourable ADMET assessments...The integrated approach of this study underscores the efficacy of 2D-QSAR modelling. It identifies LdGlyRS as a promising leishmaniasis target, offering a robust strategy for discovering and optimizing anti-leishmanial compounds to address the critical need for improved treatments."

Journal • Infectious Disease

Targeting genetic dependencies exposes diffuse midline glioma cell of origin vulnerabilities (SNO 2024) - "To exploit genetic dependencies while maintaining compliance and therapeutic benefit, we optimized combinations of clinically relevant PI3K inhibitors (paxalisib, GCT007, everolimus) with the antiglycemic drug metformin to restore glucose homeostasis and decrease DMG insulin receptor activity in vivo, extending the survival of DIPG xenograft models...The brain-penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of DIPG xenograft models, including those mimicking disease progression, with further benefits potentiated using metformin in a multimodality approach...In parallel, combined PI3K/mTOR and PDGFRA inhibition using paxalisib and avapritinib synergistically extended the survival of patient-derived xenograft models, showing the preclinical relevance of simultaneously targeting these vulnerabilities. Together, we reveal that therapeutic inhibition of PI3K/mTOR and compensatory PKC signaling, while mitigating side..."

IO biomarker • Brain Cancer • CNS Tumor • Diabetes • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • H3-3A • IR • PD-1 • PDGFRA • PD-L1 • PIK3CA

Epoxytiglianes induce keratinocyte wound healing responses via classical protein kinase C activation to promote skin re-epithelialization. (PubMed, Biochem Pharmacol) - "The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors...PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51-151 nM. PKC-α inhibitor, Ro 31-8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses...Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin."

Journal • Oncology • CCNB1 • CDKN1A • KRT17 • MMP1 • MMP10 • MMP7 • PRKCB

ENGAGE: A Trial of Enzastaurin Plus Temozolomide During and Following Radiation Therapy in Patients With Newly Diagnosed Glioblastoma With or Without the Novel Genomic Biomarker, DGM1 (clinicaltrials.gov) - P3 | N=260 | Completed | Sponsor: Denovo Biopharma LLC | Active, not recruiting ➔ Completed | Trial completion date: Jun 2025 ➔ Feb 2024 | Trial primary completion date: Jun 2025 ➔ Feb 2024

Biomarker • Trial completion • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MGMT