talmapimod (SCIO-469) / J&J - LARVOL DELTA

Bioinformatic approach for repurposing immunomodulatory drugs for lepromatous leprosy. (PubMed, Int J Mycobacteriol) - "Consistently, glucosamine, binimetinib, talmapimod, dilmapimod, andrographolide, and VX-702 might have a possible beneficial effect coupled with LL treatment. Based on our drug repurposing analysis, immunomodulatory drugs might have a promising potential to be explored further as therapeutic options or to alleviate symptoms in LL patients."

Immunomodulating • Journal • Oncology • IFNG • IL1B

CNS-Active p38α MAPK Inhibitors for the Management of Neuroinflammatory Diseases: Medicinal Chemical Properties and Therapeutic Capabilities. (PubMed, Mol Neurobiol) - "In addition, a detailed analysis of the previously released X-ray crystal structure of the inhibitors in the active site of the p38α MAPK enzyme revealed that some residues such as Met109 play a critical role in the occurrence of effective interactions by constructing strong H-bonds. This study can encourage scientists to focus more on the design, production, and biological evaluation of new central nervous system (CNS)-active p38α MAPK inhibitors in the future."

Journal • Review • CNS Disorders • Inflammation

Network-Based In Silico Analysis of New Combinations of Modern Drug Targets with Methotrexate for Response-Based Treatment of Rheumatoid Arthritis. (PubMed, J Pers Med) - "New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy."

Journal • Review • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • DHFR • NLRP3 • SYK • TYMS

Synthesis and Preclinical Positron Emission Tomography Imaging of the p38 MAPK Inhibitor [C]Talmapimod: Effects of Drug Efflux and Sex Differences. (PubMed, ACS Chem Neurosci) - "Blocking studies with a structurally dissimilar p38α/β inhibitor, neflamapimod (VX-745), and displacement imaging studies with talmapimod were attempted in elacridar-pretreated rodents, but neither compound displaced radiotracer uptake in the brain of either sex. An MDCK-MDR1 assay suggests that talmapimod is likely to suffer from drug efflux in humans as well as rodents. Future efforts should focus on radiolabeling p38 inhibitors from other structural classes to avoid P-gp efflux and non-displaceable binding."

Journal • Preclinical • CNS Disorders • ABCB1

Erythrocyte mitogen-activated protein kinases mediate hemolytic events under osmotic and oxidative stress and in hemolytic diseases. (PubMed, Cell Signal) - "Conversely, hypo-osmotic shock induced MAPKAPK2 and RSK2 phosphorylation, which was significantly inhibited by SCIO469 or CMPD1...Furthermore, p38 MAPK inhibition was associated with decreased hemolysis in response to diamide treatments or osmotic shock, and with decreased erythrocyte sickling under experimental hypoxia. These findings provided insights into MAPK-mediated signaling pathways that regulate erythrocyte function and hemolysis in response to extracellular stressors or human diseases."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • MAP2K3 • MAPKAPK2 • RPS6KA3 • SOX9

Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents. (PubMed, J Enzyme Inhib Med Chem) - "Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC=1.95 µM) and COX-2 (IC=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug."

Journal

High-level expression of ARID1A predicts a favourable outcome in triple-negative breast cancer patients receiving paclitaxel-based chemotherapy. (PubMed, J Cell Mol Med) - "The pharmaceutical inhibition with p38MAPK-specific inhibitor SCIO-469 revealed that p38MAPK-related signalling axis regulates ARID1A expression and thereby modulates paclitaxel sensitivity in TNBC cells. These findings suggest that ARID1A could be used as a prognostic factor to estimate the pathological complete response for TNBC patients who decide to receive paclitaxel-based chemotherapy."

Clinical • Journal