Tyrisa (darapladib) / GSK - LARVOL DELTA

Pla2g7 regulates bone homeostasis via Alox12/12-HETE/Gpr31 signaling axis. (PubMed, Nat Commun) - "Inhibition of Pla2g7 by Darapladib impaired both human and mice osteoclast differentiation, meanwhile, Pla2g7-deficient mice showed higher bone mass and restored the ovariectomy-induced bone loss...Its metabolite 12-HETE (12-hydroxyeicosatetraenoic acid) activated Gpr31 to regulate osteoclast formation via p38 MAPK pathway and mitochondrial energy metabolism. Collectively, our study uncovers an Alox12/12-HETE/Gpr31 axis that regulates Pla2g7-induced osteoclast differentiation, and provides a new insight for osteoporosis treatment."

Journal • Osteoporosis • Rheumatology • LA2G7

Beyond Lipids and Platelets: A Review of Anti-Inflammatory Strategies in Secondary Prevention of Acute Coronary Syndromes. (PubMed, J Clin Med) - "Colchicine, now FDA-approved for cardiovascular risk reduction, lowered major adverse cardiovascular events in COLCOT and LoDoCo2. Canakinumab (IL-1β inhibition) reduced recurrent events in proportion to IL-6 and hsCRP suppression, while ziltivekimab (IL-6 inhibition) achieved profound biomarker reductions but remains investigational. Early-phase studies of anakinra (IL-1 receptor antagonist) and dapansutrile (oral NLRP3 inhibitor) showed anti-inflammatory effects in early trials, whereas varespladib and darapladib illustrated the challenges of targeting lipid-associated pathways...Additional emerging avenues include triptolidiol, dasatinib, and BTK or JAK/STAT inhibitors, while novel approaches, such as nanozyme delivery systems and CRISPR-based editing, extend the therapeutic horizon. This review highlights the potential of inflammation-targeted therapies to advance secondary prevention in ACS by integrating current evidence and perspectives on future therapeutic..."

Journal • Review • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Immunology • Inflammation • Myocardial Infarction • CRP • IL1B • NLRP3

Different eGFR markers and prediction of cardiovascular risk. (PubMed, J Intern Med) - "In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value."

Journal • Atherosclerosis • Cardiovascular • Nephrology • Renal Disease • CST3

PLA2 driven lipid signaling drives ARMS tumorigenic cell properties. (PubMed, Cell Commun Signal) - "PLA2-mediated lipid remodelling supports TIC by promoting linoleic acid-linked lipid signalling. PLA2 inhibition impairs self-renewal, motility, and tumorigenic potential, highlighting it as a promising therapeutic target in ARMS. These findings uncover lipid remodelling as a key metabolic adaptation in ARMS TICs, independent of canonical energy pathways, with implications for targeting the stem-like compartment in pediatric sarcomas."

Journal • Metabolic Disorders • Movement Disorders • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD36 • PPARG • SCARB1

Preliminary assessment of drug repurposing against virus-associated primary effusion lymphoma. (PubMed, J Microbiol Biol Educ) - "We demonstrate proper quantitative interpretation of the data by using ethacrynic acid, quizartinib, and darapladib as examples. We hope that this practical experimental pipeline will spread awareness of the potential of drug repurposing, especially for diseases like PEL that have unmet clinical needs."

Journal • Epstein-Barr Virus Infections • Hematological Malignancies • Kaposi Sarcoma • Lymphoma • Oncology • Sarcoma • Solid Tumor

Activation of the Lp-PLA2/LPC axis triggers endothelial ferroptosis to drive diabetic kidney disease. (PubMed, Free Radic Biol Med) - "We identify the Lp-PLA2/LPC axis as a novel activator of endothelial ferroptosis in DKD. Pharmacological blockade with Darapladib protects the kidney by inhibiting this iron-dependent cell death, providing a mechanistically grounded therapeutic strategy independent of glycemic control."

Journal • Diabetes • Diabetic Nephropathy • Nephrology • Renal Disease • ACSL4 • GPX4 • ICAM1 • NOS3

Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy. (PubMed, Cell Mol Immunol) - "Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CTSB • LA2G7

Contribution of individual phospholipase A2 enzymes to the cleavage of oxidized phospholipids in human blood plasma‡. (PubMed, J Lipid Res) - "In contrast to truncated species, degradation of full-length OxPLs with > 3 extra oxygens were only minimally inhibited by darapladib. These data provide further insights into the mechanisms regulating circulating levels of OxPLs and lipid mediators generated by PLA2 cleavage of OxPLs, namely oxylipins and LysoPC."

Journal • PRDX6

White blood cell counts can predict 4-year cardiovascular disease risk in patients with stable coronary heart disease: a prospective cohort study. (PubMed, Front Cardiovasc Med) - P3 | "This study included Asian participants (n = 1,933) from the prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, which involved 15,828 patients with stable coronary heart disease with 3-5 years of follow-up on optimal secondary preventive treatment...In patients with stable coronary heart disease, higher WBC counts were associated with a heightened risk for the primary or secondary outcomes. https://clinicaltrials.gov/; Unique identifier NCT00799903."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Dyslipidemia • Heart Failure • Hematological Disorders • Myocardial Infarction

Predictive and therapeutic value of lipoprotein-associated phospholipaseA2 in sarcopenia in chronic obstructive pulmonary disease (ERS 2024) - "Darapladib treatment (25 and 50 mg/kg) rescued CS-induced musclemass loss and muscle functions. Darapladib could reverse CS-induced increase of atrogin-1 and MuRF1 expression and activation of inflammatory factors, oxidant enzymes and NF-κB signaling.ConclusionsSerum Lp-PLA2 level was significantly elevated in patients with COPD, especially in sarcopenic patients with COPD, which could be a potential indicator for sarcopenia."

Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Sarcopenia • FBXO32

Lipoprotein-associated phospholipase A2 (Lp-PLA2) : relevant biomarker and therapeutic target? (PubMed, Ann Pharm Fr) - "Despite the disappointing results of clinical trials using the Lp-PLA2 inhibitor darapladib, new pathophysiological, epidemiological and genetic data have enabled the development of new inhibitors. Recent studies also show that Lp-PLA2 is involved in vascular inflammation-related diseases other than atherosclerosis (ischemic stroke, Alzheimer's disease and vascular dementia, diabetes, cancers…), and inhibition of Lp-PLA2 could have beneficial therapeutic in these diseases. This review aims to present new data on Lp-PLA2 and to evaluate its current interest as a biomarker but also as a therapeutic target."

Biomarker • Journal • Review • Alzheimer's Disease • Atherosclerosis • Cardiovascular • CNS Disorders • Dementia • Diabetes • Dyslipidemia • Inflammation • Ischemic stroke • Metabolic Disorders • Oncology

Predictive and therapeutic value of lipoprotein-associated phospholipaseA2 in sarcopenia in chronic obstructive pulmonary disease. (PubMed, Int J Biol Macromol) - "Lp-PLA2 could be a potential indicator for sarcopenia in COPD. Darapladib, an Lp-PLA2 inhibitor, can alleviate CS-induced skeletal muscle dysfunction and represents a potential therapeutic for sarcopenia in COPD."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • Sarcopenia • FBXO32

Combination of theoretical analysis and experiments: Exploring the role of PLA2G7 in human cancers, including renal cancer. (PubMed, Heliyon) - "Treatment with a PLA2G7 gene inhibitor (darapladib) significantly decreased the viability of ACHN and 786-O cell lines. Additionally, we observed an association between PLA2G7 mRNA levels and various drug sensitivity. Our study suggests that PLA2G7 has the potential to serve as a valuable biomarker and therapeutic target for cancer, particularly in the context of renal cancer."

Journal • Tumor mutational burden • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Kidney Cancer • Lymphoma • Melanoma • Microsatellite Instability • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • LA2G7 • MSI • TMB

Inhibiting PLA2G7 reverses the immunosuppressive function of intratumoral macrophages and augments immunotherapy response in hepatocellular carcinoma. (PubMed, J Immunother Cancer) - "Macrophage-specific PLA2G7 serves as a novel biomarker capable of prognosticating immunotherapy responsiveness and inhibiting PLA2G7 has the potential to enhance the efficacy of ICB therapy for HCC."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor • CD8 • LA2G7

The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism. (PubMed, Nat Commun) - "Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment."

Journal • Metabolic Disorders • Oncology • GPX4

"Remember darapladib? Curious how that reads thru here" (@BiotechElmo)

"Did darapladib reduce CRP? I don’t think so https://t.co/BYZMEdhtVL" (@AbbateAntonio)

Serum Neurofilament Light Chain in Patients With Atrial Fibrillation. (PubMed, J Am Heart Assoc) - P3 | "Methods and Results In this observational study, sNFL was analyzed in 280 patients with AF and 280 controls without AF matched for age, sex, and diabetes status within the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial...Anticoagulation treatment did not affect sNFL levels. Trial Registration ClinicalTrials.gov NCT00799903."

Journal • Atherosclerosis • Atrial Fibrillation • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders

Examining anti-inflammatory therapies in the prevention of cardiovascular events: protocol for a systematic review and network meta-analysis of randomised controlled trials. (PubMed, BMJ Open) - "These include (but are not limited to): non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, prednisone, methotrexate, canakinumab, pexelizumab, anakinra, succinobucol, losmapimod, inclacumab, atreleuton, LP-PLA (darapladib) and sPLA (varespladib). The findings will be disseminated through a peer-reviewed journal. CRD42022303289."

Journal • Retrospective data • Review • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure • Immunology • Inflammation • Myocardial Infarction

Screening the Tocriscreen™ bioactive compound library in search for inhibitors of Candida biofilm formation. (PubMed, APMIS) - "Together, these data provide new insights into antifungal management possibilities for Candida biofilms."

Journal

Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target. (PubMed, Cell Rep) - "Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance."

Journal • Infectious Disease • Malaria • PRDX6

Integrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7 macrophages in pulmonary fibrosis. (PubMed, Pharmacol Res) - "We performed additional single-cell RNA-seq analysis to identify analogous macrophage population in bleomycin (BLM)-induced mouse pulmonary fibrosis models. Moreover, PLA2G7 is regulated by STAT1, and pharmacological inhibition of PLA2G7 by Darapladib ameliorates pulmonary fibrosis in BLM-induced mice. The results of this study support the view that PLA2G7 macrophage subpopulation contributes importantly to the pathogenesis of PF, which provides a potential way for targeted therapy."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • STAT1

Reproductive interference and Satyrisation: mechanisms, outcomes and potential use for insect control. (PubMed, J Pest Sci (2004)) - "We synthesise the key factors affecting the expression of Satyrisation and explore how they have potential utility in developing new routes for the management and control of harmful insects. We consider how Satyrisation might interact with other control mechanisms, and conclude by outlining a framework for its use in control, highlighting some of the important next steps."

Journal • Review • Infertility

Targeting Viral Ion Channels: A Promising Strategy to Curb SARS-CoV-2. (PubMed, Pharmaceuticals (Basel)) - "In particular, darapladib and flumatinib, both 3a blockers, displayed potent antiviral activity. Furthermore, appreciable synergism between flumatinib and several E blockers was identified in a concentration regime in which the compounds are present in human plasma following oral administration. Taken together, targeting ion channels represents a promising approach to both augment and complement our antiviral arsenal against COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Body Mass Index and Association With Cardiovascular Outcomes in Patients With Stable Coronary Heart Disease - A STABILITY Substudy. (PubMed, J Am Heart Assoc) - P3 | "METHODS AND RESULTS The prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial included 15 828 patients with stable coronary heart disease with 3 to 5 years' follow-up on optimal secondary preventive treatment...Underweight with BMI of <20 kg/m and very high BMI of ≥35 kg/m were strong risk markers for poor prognosis. REGISTRATION URL: https://clinicaltrials.gov/; Unique identifier NCT00799903."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Diabetes • Dyslipidemia • Genetic Disorders • Heart Failure • Hypertension • Metabolic Disorders • Obesity • GDF15