sotrastaurin (AEB071) / Novartis - LARVOL DELTA

From Bench to Bytes: Computational Tools Illuminate DAG-induced Negative Feedback in Gq-PLC Signaling, With PKC Isoforms as Tuning Knobs (ATS 2025) - "A subset of experiments were conducted in which cells were pretreated with subtype-specific PKC inhibitors (Go6976 for conventional and VTX-27 for novel), or pan-PKC inhibitors (Sotrastaurin and BisI), along with DGKi, prior to measuring Ca2+ levels...These findings highlight the complex regulation of Gq-signal transduction by PKC isoforms dictated by a tight spatio-temporal balance of second messenger signaling in ASM. This research provides new insights into Gq-DAG-PKC signaling and its role in ASM contraction with implications for a variety of cell types and diseases in which Gq signaling is pivotal."

Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • DGKI

Protein Kinase C Inhibition Overcomes Targeted Therapy Resistance in Cutaneous Melanoma. (PubMed, Exp Dermatol) - "Thus, targeting the non-canonical WNT signalling pathway via combinatorial PKC and MAPK pathway inhibition is beneficial for therapy-resistant cutaneous melanoma combating tumour heterogeneity in vivo. With our study, we are providing an alternate treatment strategy we think is worth investigating as future clinical interventions in cutaneous melanoma."

Journal • Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • WNT5A

PHGDH acts as an RNA-binding protein to stabilize PRKCD mRNA and promote hepatocellular carcinoma progression (APASL 2025) - "In hydrodynamic HCC models, the combination of the PRKCD inhibitor sotrastaurin and sorafenib significantly reduced tumor growth. This study identified PHGDH's interaction with mRNA and reported that PHGDH enhances PRKCD protein levels by stabilizing its mRNA, which facilitates mitophagy and supports HCC progression. Our findings reveal a novel function of PHGDH and establish a mechanistic link between cellular metabolism, RNA regulation and mitophagy. Targeting PHGDH's RNA-binding activity offers a unique therapeutic strategy for HCC treatment."

Hepatocellular Cancer • Oncology • Solid Tumor • PHGDH

High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia. (PubMed, Blood) - "Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK cell transition to an activated state and suppressed the expression of IFN-γ by NK cells, thus preventing IFN-γ mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK cell mediated killing, with potential clinical applications especially in patients with advanced phase CML."

IO biomarker • Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • IFNG

Comprehensive Drug Profiling and CRISPR Screening Reveal Essential Pathways for NK Cell Cytotoxicity (ASH 2024) - "In addition, pevonedistat, daporinad, and bryostatin 1 enhanced NK cell activity, whereas sotrastaurin showed strong NK cell-inhibiting effects...Various NAMPT inhibitors (KPT-9274, GMX1778 and LSN3154567) not included in the original screens showed similar effects to daporinad in AML and ALL cell lines...In conclusion, our study identifies PKC, NAMPT, and NEDD8 having an essential role in controlling NK cell-mediated killing and suggests potential compounds to enhance NK cell effectiveness in treating hematological malignancies. These findings offer insights into developing combination immunotherapy strategies to improve treatment outcomes."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Myeloid Leukemia • Diffuse Large B Cell Lymphoma • Gene Therapies • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CXCR4 • IFNG • IL2RA • LGALS3 • NAMPT • NQO1

Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress. (PubMed, iScience) - "A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • LATS1

Progress in Research on the Mechanisms and Interventions of Phlebitis from the Perspective of Vascular Endothelial Cell and Signaling Pathway. (PubMed, J Inflamm Res) - "Preventive and curative interventions included α-solanine, baicalein, escin, intermedin, Y15, micro-ribonucleic acid-223, sotrastaurin, cimetidine, aescin, resveratrol, α-chaconine, Chahuang ointment, QingLuoTongMai, Mailuo Shutong, and N-acetylcysteine. These findings improve our understanding of the molecular targets of interventions and help identify effective candidates for the prophylaxis and treatment of phlebitis. Vascular health and risk management should be considered when initiating intravenous administration."

Journal • Review • CTNNB1 • GBP5 • JAK2 • NLRP3 • PRKCB • PRKCH • STAT3

Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers. (PubMed, Am J Cancer Res) - "In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers."

Journal • Lung Cancer • Oncology • Solid Tumor

Trial of AEB071 in Combination With BYL719 in Patients With Melanoma (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Columbia University | Unknown status ➔ Completed

Combination therapy • Metastases • Trial completion • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Darovasertib, a novel treatment for metastatic uveal melanoma. (PubMed, Front Pharmacol) - "Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma."

Journal • Metastases • Review • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma. (PubMed, Front Oncol) - P1/2 | "Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated."

Journal • Metastases • P1 data • Eye Cancer • Fatigue • Gastrointestinal Disorder • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma (Front Oncol) - P1b/2 | N=38 | NCT01801358 | Sponsor: Array Biopharma, now a wholly owned subsidiary of Pfizer | "Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested....Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1."

P1 data • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Skin Cancer • Solid Tumor • Uveal Melanoma

Betacellulin regulates gap junction intercellular communication by inducing the phosphorylation of connexin 43 in human granulosa-lutein cells. (PubMed, J Ovarian Res) - "BTC promptly induced the phosphorylation of connexin 43 at Ser368, leading to decreased GJIC activity in hGL cells. The BTC-induced cellular activities were most likely driven by the EGFR-mediated PKC-dependent signaling pathway. Our findings shed light on the detailed molecular mechanisms by which BTC regulates the process of oocyte meiotic resumption."

Journal • Gynecology • BTC • EGFR • ERBB4

Loss of DJ-1 function contributes to Parkinson's disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation. (PubMed, Acta Pharmacol Sin) - "The PKC inhibitor sotrastaurin or the JNK inhibitor SP600125 completely inhibited DJ-1 deficiency-induced EGR1 and MAO-B expression in N2a cells. Moreover, the MAO-B inhibitor rasagiline inhibited mitochondrial ROS generation and rescued neuronal cell death caused by DJ-1 deficiency, especially in response to MPTP stimulation in vitro and in vivo. These results suggest that DJ-1 exerts neuroprotective effects by inhibiting the expression of MAO-B distributed at the mitochondrial outer membrane, which mediates DA degradation, ROS generation and mitochondrial dysfunction. This study reveals a mechanistic link between DJ-1 and MAO-B expression and contributes to understanding the crosslinks among pathogenic factors, mitochondrial dysfunction and oxidative stress in PD pathogenesis."

Journal • Preclinical • CNS Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • EGR1 • RACK1

Comprehensive bioinformatics and experimental analysis of SH3PXD2B reveals its carcinogenic effect in gastric carcinoma. (PubMed, Life Sci) - "Our study strongly suggests that SH3PXD2B is a carcinogenic molecule that can be used as a biomarker for GC detection, prognosis, treatment design, and follow-up."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ADAM15 • SH3PXD2B

Distinct Protein Kinase C isoforms drive the cell cycle re-entry of two separate populations of neonatal rat ventricular cardiomyocytes. (PubMed, Am J Physiol Cell Physiol) - "Sotrastaurin (conventional/novel PKC isoform inhibitor) administration to PDBu/SB203580-treated NNVMs significantly attenuated the density of nestin-NNVMs (PDBu/SB203580/sotrastaurin, 8±10; n=4) and nestin-NNVMs (PDBu/SB203580/sotrastaurin, 64±30; n=4) that incorporated 5-bromo-2'-deoxyuridine. These data reveal that the neonatal rat heart contains at least two separate populations of NNVMs that re-enter the cell cycle and the preferential appearance of nestin- or nestin-NNVMs is driven by distinct PKC isoforms in the presence of SB203580."

Journal • Preclinical • CDKN2A • NES • RUNX1

Protein Kinase C Inhibitors Reduce SARS-CoV-2 Replication in Cultured Cells. (PubMed, Microbiol Spectr) - "Four pan-PKC inhibitors, Go 6983, bisindolylmaleimide I, enzastaurin, and sotrastaurin, reduced the replication of a SARS-CoV-2 replicon in both BHK-21 and Huh7 cells. These PKC inhibitors interfere with an early step of viral infection. Therefore, the rapid and prominent antiviral effect of PKC inhibitors underscores that they are promising antiviral agents and suggests that PKCs are important host factors involved in infection by SARS-CoV-2."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

HIGH-THROUGHPUT EVALUATION OF THE POTENTIAL OF CANCER DRUGS TO ENHANCE NATURAL KILLER CELL IMMUNOTHERAPY IN CHRONIC MYELOID LEUKEMIA. (EHA 2022) - "For example, dasatinib and imatinib have been suggested to enhance NK cell cytotoxicity through regulation of activating and inhibitory receptors...The SMAC mimetics birinapant and LCL-161 were the most potent enhancers of NK cell cytotoxicity and had no effect on target cells alone...On the contrary, cytotoxicity-inhibiting drugs included previously known immunosuppressive drugs dexamethasone and prednisolone, as well as novel candidates, such as sotrastaurin, a PKC inhibitor...Conclusion We discovered novel drug classes, which had both activating and inhibitory effects on the NK cell cytotoxicity against CML cells in vitro. Defining NK cell - drug - CML cell interactions in a high-throughput setting provides a framework for future combination immunotherapies to further improve treatment-free remission in CML."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • BIRC3 • CXCL10 • CXCL11 • CXCL9 • NFKB2

Protein kinase inhibitor responses in uveal melanoma reflects a diminished dependency on PKC-MAPK signaling. (PubMed, Cancer Gene Ther) - "In this study, we examined the signaling and functional effects of two PKC inhibitors (AEB071 and IDE196) in a panel of UM cell models. The differences in UM cell responses to PKC inhibition were not attributable to the degree or timing of PKC suppression or inhibition of the downstream mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3-kinase (PI3K) pathways. Instead, UM cell show complex, PKC-independent signaling pathways that contribute to their survival and resistance to targeted therapies."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

Protein kinase C targeting of luminal (T-47D), luminal/HER2-positive (BT474), and triple negative (HCC1806) breast cancer cells in-vitro with AEB071 (Sotrastaurin) is efficient but mediated by subtype specific molecular effects. (PubMed, Arch Gynecol Obstet) - "A combined targeting of PKC and a subtype specific driver molecule might complement specified breast cancer treatment."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • NGFR

A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma. (PubMed, Cancers (Basel)) - "Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3-51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed."

Clinical • Journal • P1 data • Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ • PIK3CA

Endothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood Vessels. (PubMed, Arterioscler Thromb Vasc Biol) - "Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCβ3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype."

Journal • Developmental Disorders • Genetic Disorders • GNAQ

β-Hydroxybutyrate impairs neutrophil migration distance through activation of a protein kinase C and myosin light chain 2 signaling pathway in ketotic cows. (PubMed, J Dairy Sci) - "To confirm this hypothesis, sotrastaurin (Sotra)-a specific inhibitor of protein kinase C (PKC), which is the core regulator of cell contraction-was used with or without BHB treatment in vitro...Overall, the present study revealed that high concentrations of blood BHB impaired PMN migration distance through inhibition of the trailing edge contraction, mediated by enhancing the activation of PKC-MLC2 signaling. These findings help explain the dysfunctional immune state in ketotic cows and provide information on the pathogenesis of infectious diseases secondary to ketosis."

Journal • Infectious Disease • PRKCA • RHOA

[VIRTUAL] PKC-theta modulates myosteatosis, muscle function, atrophy, and survival in murine pancreatic ductal adenocarcinoma (AACR 2021) - "Plasma from KPC-tumor bearing mice was used to treat C2C12 myotubes, with or without the PKC inhibitor Sotrastaurin...Prkcq null tumor-bearing mice also demonstrated increased survival versus wildtype controls (p<0.001). Our data suggest that chronic lipolysis associated with PDAC promotes myosteatosis and PKC-θ activation in muscle which promotes muscle dysfunction and wasting and further that inhibition of PKC-θ in muscle may be a beneficial treatment for PDAC cachexia."

Preclinical • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IL6R • KRAS

Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures. (PubMed, Nat Commun) - "We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • NOTCH1