NSC23766 / University of Oslo - LARVOL DELTA

Anacardic acid, a histone acetyltransferase inhibitor, stimulates hemolysis and eryptosis through energy depletion and calcium accumulation. (PubMed, Acta Pharm) - "Co-treatment of AA with ATP, acetylsalicylic acid, NSC23766, or polyethylene glycol conferred significant cytoprotective effects. AA is cytotoxic to erythrocytes, causing both hemolysis and eryptosis, through non-genomic mechanisms involving Ca2+ signalling, metabolic exhaustion, K+ depletion, shrinkage and elliptocytic morphological aberrations. This toxic effect is sensitive to cyclooxygenase and Rac1 GTPase inhibition."

Journal • Hematological Disorders • Oncology • RAC1

PACSIN2 regulates mercaptopurine cytotoxicity and cellular biomechanics through Rac1 modulation in intestinal epithelial cells. (PubMed, Front Pharmacol) - "Cytotoxicity was evaluated by MTT assay following exposure to MP and the Rac1 inhibitor NSC23766. These findings suggest that PACSIN2 modulates MP response by regulating Rac1 levels and cytoskeletal integrity, providing a molecular basis for the clinical association between PACSIN2 and thiopurine-related gastrointestinal toxicity. These insights may contribute to the development of personalized approaches to optimize thiopurine therapy in pediatric patients."

Journal • Acute Lymphocytic Leukemia • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Inflammation • Inflammatory Bowel Disease • Leukemia • Oncology • Pediatrics • RAC1

Metabolic Exhaustion, p38 MAPK/Rac1 GTPase/MLKL Signaling, and Ca2+ Influx Mediate Solasodine-Triggered Eryptosis. (PubMed, Physiol Res) - "Co-treatment of erythrocytes with SOL and SB203580, NSC 23766, necrosulfonamide, caffeine, and melatonin significantly inhibited SOL-induced PS translocation. In conclusion, SOL is a novel pro-eryptotic compound whose activity is mediated through energy exhaustion, Ca2+ influx, and cytosolic KCl depletion, and requires p38 MAPK/Rac1 GTPase/MLKL signaling. Metabolic substrates, cation channel modulators, and targeted inhibition provide protective adjuncts to improve the therapeutic index of SOL as it advances toward translational applications."

Journal • Chemotherapy-Induced Anemia • Hematological Disorders • Oncology • ANXA5

PKC Inhibition by Gö6976 Promotes Osteogenic Differentiation of Dental Follicle Cells Involving Rho-Dependent Pathway Dynamics. (PubMed, Biomedicines) - "The impact of RhoGTPase signaling was tested using inhibitors (NSC23766, Y27632, Rhosin) and the activator Geranylgeranyl pyrophosphate (GGPP)...This was confirmed by simvastatin-mediated regulation of Rho expression, which was fully reversed by simultaneous treatment with Gö6976... These findings indicate that RhoGTPase signaling, particularly RhoA, is a critical downstream mediator required specifically for the Gö6976-enhanced osteogenic effect in DFCs. We conclude that Gö6976 exerts its stimulatory effect on mineralization by activating RhoGTPases and suppressing the osteogenesis inhibitor SOST, providing a context-dependent mechanism for accelerated differentiation rather than driving basal osteogenesis."

Journal • RHOA • SOST

Targeting RAC1 in glioblastoma: prognostic value, immune landscape, and small molecule therapeutic potential. (PubMed, Front Oncol) - "NSC23766 suppressed GBM cell proliferation, migration, and invasion without altering total RAC1 protein, confirming dependence on RAC1 activation state. Palbociclib inhibited GBM cell viability in a dose- and time-dependent manner. RAC1 serves as a prognostic biomarker and therapeutic stratification indicator in GBM, marking IFN-responsive tumor subpopulations that may benefit from CDK4/6 inhibitor-based strategies rather than ICI monotherapy."

IO biomarker • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • IFNG • RAC1

A novel therapeutic strategy for cholemic nephropathy: mineralocorticoid receptor antagonists attenuate bile acid–induced renal injury in vivo and in vitro via the rac1–mineralocorticoid receptor pathway (EASL 2026) - " Sixty male Wistar rats were randomly assigned to three groups: sham operation, BDL without treatment, and BDL with spironolactone treatment (100 mg/kg body weight/day) for 28 days...HK-2 cells were exposed to a bile acid cocktail reflecting this patient-specific profile, with or without potassium canrenoate and/or the Rac1 inhibitor NSC23766... These findings demonstrate a significant protective effect of mineralocorticoid receptor antagonists in experimental cholemic nephropathy, both in vivo and in vitro. Beyond the classical aldosterone–MR axis, activation of the Rac1–MR signaling pathway appears to play a critical role in bile acid–induced renal injury. Further studies are warranted to elucidate the therapeutic potential of targeting this pathway in cholestasis-associated kidney disease."

Preclinical • Cholestasis • Hepatology • Nephrology • Renal Disease • RAC1

Stimulation of Eryptosis and Hemolysis by Adrenic Acid Involves Oxidative Stress, Calcium Elevation, and Metabolic Collapse. (PubMed, Int J Mol Sci) - "While guanosine, heparin, and NSC 23766 prevented eryptosis and hemolysis, melatonin, ATP, adenine, and L-NAME only prevented eryptosis...ADR induces erythrocyte membrane injury and eryptosis through Ca2+ elevation, oxidative stress, and metabolic exhaustion subject to inhibition by the Rac1 GTPase/NOS/COX pathway. Altogether, these findings present a novel mechanistic link between lipid dysregulation and RBC dysfunction which may improve dietary strategies to prevent and manage CVD."

Journal • Cardiovascular • Hematological Disorders • ANXA5 • RAC1

Cannabidiolic acid causes a defect in tail retraction of migrating MDA-MB-231 cells: Possible involvements of Rho-associated protein kinases (ROCKs) inhibition and accumulation of vinculin at the rear of migrating cells. (PubMed, J Biochem) - "CBDA stimulated lamellipodia formation at the leading edge, whereas NSC23766 (an established Rac1 inhibitor) completely blocked this elongated morphology. Biochemical analyses, including time-lapse imaging and confocal laser scanning microscopy, revealed that, compared to Y-27632, CBDA can induce impaired tail retraction coupled with unidirectional elongation of the cell body, upregulate the mRNA expression of DIAPHs, and accumulate vinculin, an adhesion protein, at the trailing edge without affecting its expression. These results indicate the potential of CBDA as a new candidate for the synthesis of ROCK inhibitors, which can evoke the directed elongation of MDA-MB-231 cells."

Journal • Breast Cancer • Oncology • Solid Tumor • RHOA • VCL

Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling. (PubMed, Nat Commun) - "Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduces survival and motility in resistant cells, inhibits in vivo Rac1 activity, and reduces tumour burden when combined with tamoxifen in a drug-refractory patient derived xenograft model. This work identifies the P-Rex1/Rac1 axis as a potential therapeutic target for late recurring ER+ breast cancer."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

Activation of the C3a-C3aReceptor-axis is associated with endothelial dysfunction and glycocalyx damage in ST-elevation myocardial infarction. (PubMed, Basic Res Cardiol) - "C3a-receptor-antagonists (SB290157 and JR14a), C5a-Receptor1-antagonism (PMX53), as well as Rac1-Inhibition (NSC23766) were used to verify pathway specificity and downstream signaling involvement. C3a:C3a-Receptor signaling drives Rac1-mediated cytoskeletal stiffening, eGC degradation, NO reduction, and leukocyte adhesion, promoting endothelial dysfunction in STEMI in both macrovascular and microvascular endothelial cells. This pathway represents a potential therapeutic target to mitigate complement-mediated vascular injury in acute myocardial infarction."

Journal • Cardiovascular • Myocardial Infarction • Reperfusion Injury • SDC1

Patient derived cancer organoids as a model to predict clinical response and drug discovery in colorectal cancer (AACR 2025) - "All plates were imaged on Day 0 and Day 2; diameter analysis was performed, and GD was determined for all treatment groups. Seven PDCO lines were treated with FOLFOX or FOLFIRI and a GD range of 0.01-1.61 with a median of 0.75 were observed... PDCOs show exciting potential as a predictive model for patient response and drug discovery. These findings need to be validated in further studies."

Clinical • Colorectal Cancer • Oncology • Solid Tumor

RAS-Related C3 Botulinum Toxin Substrate 1 Inhibition Attenuates Platelet Chemokine Activation in Diabetes Mellitus. (PubMed, Arch Razi Inst) - "The study included Swiss albino male mice pretreated with the Rac1 inhibitor NSC23766 and streptozotocin (STZ) to induce diabetes...CXCL4 levels were reduced by 80% following Rac1 inhibition (P <0.05), while CCL5 levels decreased by 55.5% (P <0.05). The current study indicates that Rac1 plays a pivotal role in releasing PLT chemokines due to diabetes-induced inflammation in several organs, and inhibiting Rac1 may represent a novel therapeutic approach to managing inflammation in diabetic individuals."

Journal • Diabetes • Inflammation • Metabolic Disorders • RAC1

Targeting geranylgeranyl diphosphate synthase suppresses interleukin-1β-driven proliferation in lung squamous cell carcinoma by inhibiting Ras homolog family member A and Rac family small GTPase 1 geranylgeranylation. (PubMed, Int J Biol Macromol) - "Critically, pharmacological inhibition abolished GGPPS-driven geranylgeranylation-dependent signaling: JSH-23 reversed both the proliferation mediated by RHOA and NF-κB p65 and the upregulation of IL1B potentiated by GGPS1 overexpression; and NSC23766 blocked the RAC1/STAT1-dependent IL1RAP activation amplified by GGPPS elevation, confirming that both axes are indispensable for GGPPS-dependent proliferation. Collectively, this GGPPS-mediated geranylgeranylation axis, converging on IL-1 pathway amplification, represents a central therapeutic vulnerability in LUSC, highlighting GGPPS as a promising macromolecular target for this recalcitrant malignancy."

Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • IL1B • IL1RAP • RAC1 • RHOA • STAT1

Design, synthesis and evaluation of novel oxadiazole-based compounds as potential Rac1 inhibitors against breast cancer. (PubMed, Eur J Med Chem) - "Further evaluation using a Rac1 inhibition assay demonstrated that two compounds bearing 2-fluorophenyl and 4-methylphenyl substituents exhibited the strongest inhibitory effects, with 81 % and 78 % inhibition at 19 μM and 12 μM, respectively, whereas NSC23766, a reported selective Rac1 inhibitor, showed 82 % activity at 100 μM...The strong agreement between docking scores and biological assay data supports the conclusion that these two compounds act as potent inhibitors of Rac1-GEF interaction, thereby interfering with Rac1-mediated oncogenic signaling. Given their strong in vitro activity and favorable selectivity, these compounds are proposed as promising hit candidates for further in vivo studies to evaluate their therapeutic potential and safety profiles."

Journal • Breast Cancer • Oncology • Solid Tumor

OTUB2 aggravates pathological cardiac hypertrophy through Rac1 activation. (PubMed, Hum Cell) - "Notably, pharmacological inhibition of Rac1 activation with NSC23766 abolished OTUB2-mediated hypertrophic responses in PE-treated cardiomyocytes. Our findings establish the OTUB2/Rac1 axis as a novel regulator of pathological cardiac hypertrophy and a potential therapeutic target for cardiac remodeling."

Journal • Fibrosis • Immunology • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • RAC1

The Rac1-USP11 feedback amplification loop: a radiation-activated engine driving radioresistance in hepatocellular carcinoma. (PubMed, Br J Cancer) - "This study identifies the Rac1-USP11 reciprocal feedback loop as a novel, self-reinforcing mechanism driving radioresistance in HCC. Targeting this loop via combined Rac1-GTP/USP11 inhibition represents a promising therapeutic strategy for radiosensitizing HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • RAC1 • USP11

NSC23766 effectively inhibited retinal neovascularization by disrupting the positive feedback loop between Rac1 and VEGFR2. (PubMed, Sci Rep) - "Notably, in an oxygen-induced retinopathy (OIR) mouse model, intravitreal injection of NSC23766 significantly attenuated RNV progression. Therefore, our findings suggest that NSC23766 is a potential therapeutic strategy for RNV by disrupting the positive feedback loop between Rac1 and VEGFR2."

Journal • Age-related Macular Degeneration • Ophthalmology • Retinal Disorders • KDR • RAC1

Vasoactivity of Rac GTPase, Cytohesin and Kinase Inhibitors in Renal Interlobar and Coronary Arteries Reveals Shared and Distinct Patterns of Inhibitory Effects in Vascular and Prostate Smooth Muscle Contraction. (PubMed, Pharmacol Res Perspect) - "Examined compounds included inhibitors for Rac GTPases (EHT1864, NSC23766), cytohesin GEFs (SecinH3), LIMK (SR7826, LIMKi3), βARKs (CMPD101), PAK (FRAX486), and ILK (Cpd22)...Findings with SecinH3 suggest an organ-selective involvement of cytohesin-2/Arf6 signaling in smooth muscle contractions. SR7826 may cause cardiovascular effects, while side-effect risks limit kinase inhibitors in non-malignant disease."

Journal • Benign Prostatic Hyperplasia • Cardiovascular • EDN1

SPARC Stabilizes Integrin α4-VCAM-1 Interactions and Is Regulated By Intracellular Rac in NPM1-Mutated AML (ASH 2024) - "Cancer Cell 2022) and set up a xenograft model treated with Venetoclax/Azacitidine (Ven/Aza) and an α-integrin α4 blocking antibody...In addition, administering the Rac inhibitor, NSC23766, downregulated SPARC expression by 3.8-fold (P = 0.0032) indicating a Rac-dependent expression...This transcriptional regulation is integrin α4 and Rac-dependent. Functionally, SPARC triggers cytoskeletal disassembly and enhances integrin α4/VCAM-1 mediated adhesion."

Acute Myelogenous Leukemia • Oncology • DNMT3A • ITGA4 • NPM1 • SPARC • VCAM1

Rac1 inhibition modulates galanin receptor-2, macrophage phenotype, and invasion in head and neck squamous cell carcinoma (CICON 2025) - "Two weeks after injection, mice were treated with an intratumoral dose of Rac1 inhibitor (NSC23766, 5nM, 3x/week, n=6)...Efferocytosis activity was surprisingly enhanced. Collectively, the results indicate that Rac1 inhibition reduces tumor aggressiveness and reprograms macrophages in the tumor microenvironment towards an anti-tumor and pro-inflammatory phenotype."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD68 • CD80 • GAL • MMP9 • PTPRC • VIM

Inhibiting Rac1 signaling alleviates DSS-induced colitis by improving inflammatory response and intestinal permeability. (PubMed, Gastroenterol Rep (Oxf)) - "Rac1 inhibitor NSC23766 attenuates symptoms, colonic inflammation, and intestinal permeability in a DSS-induced colitis model. These effects may be attributed to the suppression of inflammatory responses and DSS-induced damage of intestinal integrity."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • IL6 • MPO • OCLN

The effect and related mechanisms of RAC1 GTP on radiotherapy for hepatocellular carcinoma. (PubMed, Transl Cancer Res) - "NSC23766, a RAC1 GTP inhibitor, was employed to identify the pathway-specific effects...RAC1 overexpression portends poor HCC prognosis and mediates radioresistance through GTP-dependent activation of antiapoptotic pathways and cell cycle modulation. Targeting RAC1 GTP activity may enhance the radiosensitivity of HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • BCL2L1 • NFKBIA • RAC1

Investigation of the Rac1-SGK1 Pathway and Therapeutic Effects of Finerenone and Rac1 Inhibition in a Fabry Disease Podocyte Model (ERA 2025) - "The control group (wild type; wt) and GLA-suppressed cells (Fabry podocytes) were treated with finerenone and Rac 1 inhibitor (NSC23766). This study is the first in the literature to demonstrate the involvement of the RAC1-SGK1 pathway including increased mineralocorticoid receptor, 11β-HSD1 and NOX5 gene expression and Rac1 protein levels in Fabry podocyte damage and to show the therapeutic effectiveness of finerenone, a non- steroidal mineralocorticoid receptor antagonist, as well as Rac1 inhibition. We believe that finerenone therapy, as a podocyte-protective treatment, may be effective in preventing Fabry nephropathy in the future.Figures: Figure 1. The results of GLA gene expression and GLA protein analyses (Western Blot) Figure 2."

Fabry Disease • Genetic Disorders • Glomerulonephritis • Renal Disease • NOX5

Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. (PubMed, Elife) - "Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in +/K1431M variant cortex. Our work reveals that discrete NDD-associated Trio variants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo."

Journal • Preclinical • Autism Spectrum Disorder • Bipolar Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia • RHOA • TIAM1

TIAM1 drives prostatic branching phenotype and is a potential therapeutic target for benign prostatic hyperplasia. (PubMed, JCI Insight) - "The translational relevance of these findings is underscored by the growth inhibition observed in patient-derived BPH organoids treated with NSC23766. In conclusion, our findings identify TIAM1 as a key driver of prostatic branching and growth, and suggest that targeting TIAM1-RAC1 signaling could be a promising therapeutic strategy for BPH."

Journal • Benign Prostatic Hyperplasia • Geriatric Disorders • Hematological Malignancies • Lymphoma • Oncology • Urology • TIAM1