NSC23766 / University of Oslo - LARVOL DELTA

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

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

Docosahexaenoic Acid Promotes Eryptosis and Haemolysis through Oxidative Stress/Calcium/Rac1 GTPase Signalling. (PubMed, Folia Biol (Praha)) - "Importantly, inhibition of Rac1 GTPase activity with NSC23766 significantly reduced DHA-mediated haemolysis, as did co-administration of either sucrose or polyethylene glycol 8,000. Conversely, the presence of 125 mM KCl and urea without extracellular Ca2+ significantly exacerbated DHA toxicity. In conclusion, this is the first report that identifies key biochemical mechanisms underlying the cytotoxic effects of DHA in RBCs, promoting further development and validation of DHA in anticancer therapy."

Journal • Hematological Disorders • Oncology • ANXA5 • RAC1

Galangin Triggers Eryptosis and Hemolysis Through Ca2+ Nucleation and Metabolic Collapse Mediated by PKC/CK1α/COX/p38/Rac1 Signaling Axis. (PubMed, Int J Mol Sci) - "Notably, co-treatment of cells with GAL and staurosporin, D4476, or acetylsalicylic acid prevented PS externalization whereas only the presence of SB203580 and NSC23766 rescued the cells from GAL-induced hemolysis. Ca2+ nucleation and metabolic collapse mediated by PKC/CK1α/COX/p38/Rac1 drive GAL-induced eryptosis and hemolysis. These novel findings carry ramifications for the clinical prospects of GAL in anticancer therapy."

Journal • Hematological Disorders • Oncology • Pain • ANXA5 • RAC1

Rac1 inhibition regenerates wounds in mouse fetuses via altered actin dynamics. (PubMed, Sci Rep) - "NSC23766, a Rac1-specific inhibitor, altered actin dynamics at the cell margin from filopodia formation to cable formation and inhibited the migration of mouse epidermal keratinocyte, PAM212, by Rac1 signaling suppression...Knocked-out Rac1 transgenic mice experienced delayed epithelialization of wounds with suppressed epidermal migration in adults; however, in fetuses, complete wound regeneration via Rac1 signal suppression was observed. Therefore, Rac1 suppression in the wound epidermis can achieve regenerative wound healing in fetuses and may be a potential candidate for healing scars."

Journal • Preclinical

GIT2 Maintains Podocyte Architecture through Suppressing Rac1 Activity and Focal Adhesion Turnover (KIDNEY WEEK 2024) - "GIT2 KD elicited cell spreading with marked lamellipodial protrusions, which was significantly attenuated by the Rac1 inhibitor NSC23766... We demonstrated that GIT2 suppresses Rac1 activity in focal adhesions and contributes to maintaining podocyte morphology and function. Furthermore, we showed that GIT2 facilitates translocation of the PTP1B to focal adhesions where it dephosphorylates p130Cas, thereby suppressing local Rac1 activity."

Renal Disease • PTPN1

Protective Effect of GIT2 against Podocyte Injury in Mice (KIDNEY WEEK 2024) - "Rac1 inhibitor NSC23766 significantly decreased ACR in UNx-DOCA/salt-treated KO mice... In the current study, we demonstrated that GIT2 protects podocytes and glomerular function against injury. GIT2 may become a new therapeutic target on the Rac1 pathway in podocytopathy."

Preclinical • Cardiovascular • Glomerulonephritis • Hypertension • Renal Disease

RBM5 induces motor neuron apoptosis in hSOD1G93A-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways. (PubMed, Brain Res Bull) - "The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • MIR141

Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. (PubMed, bioRxiv) - "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

The S-Nitrosylation of Septin2 (SNO-Septin2) axis: A novel potential therapeutic target for treating aneurysms and dissection. (PubMed, Drug Discov Ther) - "Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD."

Journal • Review • Cardiovascular • Hematological Malignancies • Lymphoma • Oncology • SEPTIN2 • TIAM1

TLR4/Rac1/NLRP3 Pathway Mediates Amyloid-β-Induced Neuroinflammation in Alzheimer's Disease. (PubMed, J Alzheimers Dis) - "Blocking the pathway by CLI095 or NSC23766 suppressed Aβ1-42-triggered activation of microglia, reduced the expression of pro-inflammatory mediators and ameliorated the cognition deficits in APP/PS1 mice. Our study demonstrated that TLR4/Rac1/NLRP3 pathway mediated Aβ-induced neuroinflammation, which unveiled a novel pathway and key contributors underlying the pathogenic mechanism of Aβ."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • NLRP3 • TLR4

Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia. (PubMed, Brain) - "Furthermore, co-administration of the Tiam1 signaling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management."

Journal • Pain • TIAM1

Cardiomyocytes, cardiac endothelial cells and fibroblasts contribute to anthracycline-induced cardiac injury through RAS-homologous small GTPases RAC1 and CDC42. (PubMed, Pharmacol Res) - "The clinical use of the DNA damaging anticancer drug doxorubicin (DOX) is limited by irreversible cardiotoxicity, which depends on the cumulative dose applied...Consistently, immunohistochemical analyses revealed that the RAC1 inhibitor NSC23766 and the pan-RHO GTPase inhibitor lovastatin reduced the level of DOX-induced residual DNA damage in both cardiomyocytes and non-cardiomyocytes in vivo. Overall, we conclude that both endothelial cells, fibroblasts and cardiomyocytes contribute to the pathophysiology of DOX-induced cardiotoxicity, with RAC1- and CDC42-regulated signaling pathways being especially relevant for DOX-stimulated DSB and DNA damage response (DDR) activation. Hence, we suggest dual targeting of RAC1/CDC42-dependent mechanisms in multiple cardiac cell types to mitigate DNA damage-dependent cardiac injury evoked by DOX-based anticancer therapy."

Journal • Cardiovascular • Oncology • CDC42 • RAC1

Hyperglycemic stress induces oxidative damage of enteric glial cells by triggering redoxosomes/p66SHC activation. (PubMed, Redox Rep) - "Moreover, inhibitors of redoxosomes, such as the RAC1 inhibitor NSC23766 and the NOX inhibitor VAS2870, effectively mitigated the hyperglycemic stress-induced oxidative damage of EGCs...Our findings suggest that the redoxosomes/p66SHC signaling is involved in the oxidative damage of EGCs during the pathological process of DGD. This signaling cascade may represent a potential therapeutic target for the treatment of DGD."

Journal • Diabetes • Gastrointestinal Disorder