GSK461364 / GSK - LARVOL DELTA

GSK461364 Inhibits NLRP3 Inflammasome by Targeting NEK7 Phosphorylation. (PubMed, Adv Sci (Weinh)) - "Specifically, that PLK1-mediated phosphorylation of NEK7, likely occurring at evolutionarily conserved serine residues (Ser221 and Ser260), is shown to enhance NEK7-NLRP3 binding, a critical step for NLRP3 inflammasome assembly. These findings not only establish GSK461364 as a novel therapeutic candidate for NLRP3-driven inflammatory diseases but also provide new insights into the regulatory mechanisms governing inflammasome activation through post-translational modification."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • NLRP3 • PLK1

Machine learning-based characterization of a PANoptosis-associated model for enhancing prognosis and immunotherapy response in lung adenocarcinoma patients. (PubMed, Discov Oncol) - "The present study developed a PRS using 101 machine learning combination algorithms, which could aid in risk stratification and prognosis for LUAD patients. The candidate drugs and target may provide new insights in the treatment of high PRS group patients."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TRPA1

LMNB1 and LMNB2 as Prognostic Risk Factors in Hepatocellular Carcinoma: Therapeutic Potential of GSK461364 via Downregulation of LMNB1 and LMNB2 Expression. (PubMed, Recent Pat Anticancer Drug Discov) - "LMNB1 and LMNB2 are prognostic factors for HCC. GSK461364 is a novel therapeutic candidate for HCC, with anti-HCC effects associated with LMNB1/2 suppression."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • LMNB1 • LMNB2

Inhibition of FOXM1 Synergizes with BH3 Mimetics Venetoclax and Sonrotoclax in Killing Multiple Myeloma Cells through Repressing MYC Pathway. (PubMed, Adv Sci (Weinh)) - "Furthermore, the PLK1-specific inhibitor GSK461364 synergizes with NB73 to inhibit MM cell growth. Interestingly, NB73 does not sensitize U266 cells, a Venetoclax-resistant t(11;14) MM cell line expressing high FOXM1, to Venetoclax treatment, which is corrected by a new-generation BH3 mimetic Sonrotoclax and ALK inhibitor Ceritinib. Collectively, targeting FOXM1 demonstrates significant potential for enhancing the efficacy of FDA-approved drugs in RRMM. These findings shed new light on the discouraging outcomes of the Phase-III CANOVA study centering Venetoclax with an encouraging molecular clue."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • FOXM1 • PLK1

NK1R Antagonist, CP-99,994 Ameliorates Dry Eye Disease via Inhibiting the Plk1-Cdc25c-Cdk1 Axis. (PubMed, J Biochem Mol Toxicol) - "Plk1 inhibitor, GSK461364 was applied to explore the treatment mechanism of CP-99,994...Moreover, Plk1 inhibitor considerably promoted the therapeutic effect of CP-99,994 on DED model by reducing the release of IL-6, IL-1β, and TNF-α. The NK1R antagonist, CP-99,994 mitigated DED symptoms via inhibiting Plk1-Cdc25c-Cdk1 axis, which served as a novel therapeutic target for DED treatment."

Journal • Dry Eye Disease • Ocular Inflammation • Ophthalmology • CDC25C • CDK1 • GNRP • IL1B • IL6 • PLK1 • TNFA

Single-cell and bulk RNA sequencing analysis reveals CENPA as a potential biomarker and therapeutic target in cancers. (PubMed, PLoS One) - "CENPA serves as a crucial biomarker for the cell cycle in cancers, offering both diagnostic and prognostic value."

Biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CENPA

Integrating network analysis with differential expression to uncover therapeutic and prognostic biomarkers in esophageal squamous cell carcinoma. (PubMed, Front Mol Biosci) - "We also identify the molecules targeting these essential hub genes, among which GSK461364 is a promising inhibitor of PLK1, BMS265246, and Valrubicin inhibitors of CDK1 and TOP2A, respectively. Notably, MMP9 emerged as a significant prognostic marker with high expression correlating with poor survival, underscoring its potential for targeted therapy. These findings enhance our understanding of ESCC pathogenesis and highlight promising avenues for treatment."

Biomarker • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Squamous Cell Carcinoma • CDK1 • MAD2L1 • MMP9 • PLK1 • TOP2A

Therapeutic Potential of PLK1, KIF4A, CDCA5, UBE2C, CDT1, SKA3, AURKB, and PTTG1 Genes in Triple-Negative Breast Cancer: Correlating Their Expression with Sensitivity to GSK 461364 and IKK 16 Drugs. (PubMed, Biochem Genet) - "The results of this study showed a significant increase in the expression level of PLK1, KIF4A, CDCA5, UBE2C, CDT1, SKA3, AURKB, and PTTG1 in TNBC compared to other BC subgroups. These genes show considerable promise as therapeutic targets for the TNBC subgroup."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKB • CDCA5 • CDT1 • ER • HER-2 • KIF4A • PGR • PLK1 • PTTG1 • UBE2C

The effect of PLK1 inhibitor in osimertinib resistant non-small cell lung carcinoma cells. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "PLK1 inhibitors have a synergistic effect with osimertinib on osimertinib-resistant NSCLC cells which indicates that they may have potential clinical value in the treatment of NSCLC patients with osimertinib resistance."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

PLK1 Regulates MicroRNA Biogenesis through Drosha Phosphorylation. (PubMed, Int J Mol Sci) - "Small RNA sequencing and qPCR validation were used to assess downstream consequences of PLK1 activity on miR biogenesis, identifying a set of ten miRs (miR-1248, miR-1306-5p, miR-2277-5p, miR-29c-5p, miR-93-3p, miR-152-3p, miR-509-3-5p, miR-511-5p, miR-891a-5p and miR-892a) whose expression levels were statistically significantly downregulated by two pharmacological PLK1 kinase domain inhibitors, RO-5203280 and GSK461364...In combination with prior studies, this work identifies Drosha S and S as major integration points for signalling by several kinases, whose relative activities will determine the relative biogenesis efficiency of different miR subsets. Identified kinase-regulated miRs have potential for use as kinase inhibitor response-predictive biomarkers, in cancer and other diseases."

Epigenetic controller • Journal • Oncology • ANKRD52 • CSNK1A1 • MIR1248 • MIR152 • MIR2277 • MIR509-3 • MIR93 • PAK5 • PLK1

BI6727 and GSK461364A, potent PLK1 inhibitors induce G2/M arrest and apoptosis against cholangiocarcinoma cell lines. (PubMed, Pathol Res Pract) - "In conclusion, pharmacologic PLK1 inhibition by BI6727 and GSK461364A blocked survival of CCA cells by several mechanisms. Our study provides evidence that BI6727 and GSK461364A could be alternative drugs and have potential implications at the clinical level for CCA therapy."

Journal • Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • CASP3 • CCNB1 • MCL1

A polo-like kinase inhibitor identified by computational repositioning attenuates pulmonary fibrosis. (PubMed, Respir Res) - "These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • PLK2

GSK461364A suppresses proliferation of gastric cancer cells and induces apoptosis. (PubMed, Toxicol In Vitro) - "Current findings suggest that GSK461364A may be a chemotherapeutic agent in patients with gastric cancer. Nevertheless, more research is needed to evaluate GSK461364A as a cancer treatment drug."

IO biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ANXA5 • BAX • BCL2 • CASP3 • PLK1

3D cell-culture strategy for screening novel agents in Fanconi anemia chemoprevention (AACR 2023) - "Next, we studied metformin (Met) and pioglitazone (Pio)(agents in current oral cancer prevention studies) combined with G2/M blockade inhibitors, MK1775 (Wee1 kinase inhibitor) and GSK461364 (PLK inhibitor) in FA1s. Differentiation was indicated by upregulation panKeratin and Transglutaminase-3. We conclude combination therapies with high interest agents in FA-associated oral cancer can be performed in 3D culture systems and might confirm drug mechanisms of action, thus augmenting other standard methods of cancer drug evaluation and screening (e.g. cell proliferation and clonogenicity)."

Preclinical • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • BIRC5

Unusually High Affinity of the PLK Inhibitors RO3280 and GSK461364 to HSA and Its Possible Pharmacokinetic Implications. (PubMed, Mol Pharm) - "Binding constants to site I of HSA of 2.23 × 10 and 8.80 × 10 M were determined for RO3280 and GSK461364, respectively, at 310 K. The binding processes of RO3280 and GSK461364 to HSA are entropy- and enthalpy-driven, respectively. The positive enthalpy found for the RO3280-HSA complex formation could be related to a proton pre-equilibrium of RO3280."

Journal • PK/PD data

Definition of a Novel Cuproptosis-Relevant lncRNA Signature for Uncovering Distinct Survival, Genomic Alterations, and Treatment Implications in Lung Adenocarcinoma. (PubMed, J Immunol Res) - "Additionally, high-risk patients generally exhibited higher response to chemotherapeutic agents (cisplatin, etc.). We also predicted several small molecule compounds (GSK461364, KX2-391, etc.) for treating this subset. Accordingly, this cuproptosis-relevant lncRNA signature offers an efficient approach to identify and characterize diverse prognosis, genomic alterations, and treatment outcomes in LUAD, thus potentially assisting personalized therapy."

Biomarker • IO biomarker • Journal • Retrospective data • Immunology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD8 • TMB

Computational drug repositioning and wet-lab validation approach identifies polo-like kinase inhibitors as potential therapeutics for pulmonary fibrosis (ERS 2022) - "The experimental lung fibrosis was induced in mice by bronchial administration of bleomycin...[Results] Computational drug repositioning predicted that BI2536, a polo-like kinase (PLK) 1/2 inhibitor as a new therapeutic agent for IPF...Because the immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts, while PLK2 expression was dominant in lung epithelial cells, we next focused on GSK461364, selective PLK1 inhibitor...[Conclusion] Targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis. In addition, while in silico screening is useful, it is essential to determine the biological activities of candidates by wet-lab validation studies."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • PLK2

Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention. (PubMed, Cell Death Dis) - "We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer."

Journal • CNS Disorders • Oncology • Ovarian Cancer • Psychiatry • Solid Tumor

Computational Drug Repositioning Approach Identifies Polo-Like Kinase Inhibitors as Potential Therapeutics for Pulmonary Fibrosis (ATS 2022) - "Although the administration of BI2536, pan-PLK inhibitor, attenuated pulmonary fibrosis in bleomycin-treated mice, it apparently accelerated the body weight loss and increased mortality. On the other hand, GSK461364, selective PLK1 inhibitor, attenuated pulmonary fibrosis with acceptable mortality and weight loss...[Conclusion] These findings indicate that the targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting fibroblast proliferation without affecting epithelial cells. In addition, the computational approaches leveraging public gene expression data may be a useful method to find a novel antifibrotics."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • PLK2

Epigenetic and Immune-Cell Infiltration Changes in the Tumor Microenvironment in Hepatocellular Carcinoma. (PubMed, Front Immunol) - "The CTRP and PRISM-derived drug response data yielded four CTRP-derived compounds (SB-743921, GSK461364, gemcitabine, and paclitaxel) and two PRISM-derived compounds (dolastatin-10 and LY2606368). Epigenetic alterations of cancer-related genes in the tumor microenvironment play a major role in carcinogenesis. This study showed that epigenetic-related novel biomarkers could be useful in predicting prognosis, clinical diagnosis, and management in HCC."

Biomarker • IO biomarker • Journal • Tumor microenvironment • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • BMI1 • CBX2 • CDK1 • CTLA4 • MSI • PD-1 • TOP2A

[VIRTUAL] Use of kinase inhibitors in Fanconi anemia oral cancercell lines (AACR 2021) - "We examined metformin, pioglitazone, the polo-like kinase 1 inhibitor, GSK461364, and Wee1 kinase inhibitor, AZD1775.In single agent studies, we observed dose-dependent decreases in cell proliferation with all 4 single agents. Our current data demonstrate feasibility and preclinical efficacy of a combined agent approach for FA associated head and neck cancer. The low reported toxicity of these agents clinically allows for all of these agents to potentially move forward clinically, once additional experiments are conducted in mechanistic and animal studies."

Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • PLK1

Recent advancements on Benzimidazole: A versatile scaffold in medicinal chemistry. (PubMed, Mini Rev Med Chem) - "A number of benzimidazoles such as bendamustine, pantoprazole have been approved for the treatment of various illnesses whereas galeterone and GSK461364 are in clinical trials. The present review article gives an overview about the different biological activities exhibited by the benzimidazole derivatives as well as different methods used for the synthesis of benzimidazole derivatives for the past ten years."

Journal • Oncology

PLK1 inhibition sensitizes breast cancer cells to radiation via suppressing autophagy. (PubMed, Int J Radiat Oncol Biol Phys) - "Our findings indicate that PLK1 inhibition enhances the radiosensitivity of breast cancer cells in a manner associated with the suppression of radiation-induced autophagy. The inhibition of PLK1 represents a promising strategy for radiosensitizing breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor

Dual targeting of BTK and PLK1 causes lethal synergistic effects in mantle cell lymphoma (AACR 2018) - "...In further support of BTK inhibition for the treatment of MCL, acalabrutinib, an irreversible second-generation BTK inhibitor, was recently approved by the FDA for previously treated MCL...To identify therapies that will overcome resistance to BTK inhibition, we performed a combinational screen for ibrutinib with FDA-approved drugs and novel agents and found that combination treatment of ibrutinib with the polo-like kinase 1 (PLK1) inhibitors volasertib or GSK461364 achieved synergistic growth inhibition in both ibrutinib-sensitive and -resistant MCL cells...We are also validating the in vitro findings using patient-derived xenograft models in vivo. These data suggest that targeting PLK1 in MCL is a promising therapy and that dual targeting of BTK and PLK1 is a promising therapeutic strategy to improve MCL patient outcomes and to overcome ibrutinib resistance."

PARP Biomarker • Acute Myelogenous Leukemia • Mantle Cell Lymphoma

A specific inhibitor of polo-like kinase 1, GSK461364A, suppresses proliferation of Raji Burkitt's lymphoma cells through mediating cell cycle arrest, DNA damage, and apoptosis. (PubMed, Chem Biol Interact) - "Taken together, the present results emphasized that GSK461364A could be a useful therapeutic agent in patients with Burkitt's lymphoma. However, further studies are required to consolidate the anticancer activity of this promising compound."

IO Biomarker • Journal • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CASP3