firategrast (SB683699) / GSK - LARVOL DELTA

Determining the Effects of the Pathogenic Developmental and Epileptic Encephalopathy Patient Variant, scn1b-p.r98c, on Neuronal Excitability (AES 2024) - "Funding: NIH R37 NS076752 (LLI), T32 TR004764 (AMC) Rationale: Dravet syndrome (DS) is a devastating developmental and epileptic encephalopathy (DEE)... These results suggest that the Scn1b-p.R98C variant may confer cell type and brain region specific changes in neuronal excitability in vivo. Ongoing studies are examining potential effects of Scn1b-p.R98C heterozygosity on neuronal function as well as the effects of Scn1b-p.R98C homozygosity and heterozygosity on synaptic transmission."

Clinical • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Movement Disorders • NAV1

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis. (PubMed, Drug Saf) - "A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents."

Retrospective data • Review • CNS Disorders • Hematological Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease • Multiple Sclerosis • Oncology • Primary Immunodeficiency • Rare Diseases • Solid Tumor

Introduced the ITGB1-DT as a novel biomarker associated with five potential drugs using bioinformatics analysis of breast cancer proteomics data and RT-PCR. (PubMed, Mol Cell Probes) - "These analyses proposed that ITGB1-DT could be employed as a differentiated factor to identify breast tumor tissues in healthy samples. Besides this, Firategrast could be introduced as a potential remedial agent for breast cancer patients. Overall, from the analysis of a proteomics dataset, an integrative map was generated, and a novel biomarker that may have been implicated in the early detection of BC was introduced."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • ITGB1-DT

Comprehensive bioinformatic analysis reveals a cancer-associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer. (PubMed, BMC Cancer) - "Our study demonstrated the central role of extracellular matrix components secreted and remodeled by CAFs in gastric cancer. The gene signature we identified in this study carries high potential as a predictive tool for poor prognosis in gastric cancer patients. Elucidating the mechanisms by which the signature genes contribute to poor patient outcomes can lead to the discovery of more potent molecular-targeted agents and increase the therapeutic success in gastric cancer."

Biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CAFs • COL1A1 • COL1A2 • COL3A1 • COL5A1 • ITGA4

Targeting CXCR4, VLA4, and CXCR2 for Hematopoietic Stem Cell Mobilization (ASH 2019) - "Two examples of previously described drugs that target mechanisms of stem cell retention are Plerixafor (a CXCR4 inhibitor already in clinical use), and truncated Gro-Beta (tGroβ; a CXCR2 agonist). Firetagrast and BIO5192 are previously characterized VLA4i that have been administered to humans for indications unrelated to HSC mobilization. Our best VLA4i to date, LGB-2019, exhibited similar potency as BIO5192 in preventing the binding of sVCAM-1 to VLA-4 (IC50: 1.7nM) and was >200-fold more potent than firategrast. LGB-2019 showed increased aqueous solubility and mobilized 1.5-fold more murine LSK cells for a longer time period (peak HSC mobilization maintained for 4 hours) than BIO5192 when administered alone."

CXCR2 • CXCR4

BCR-Induced VLA-4 Activation in the TCL1 Transgenic Mouse Model for Chronic Lymphocytic Leukemia (ASH 2019) - "Mouse treatment studies were performed upon transplantation of TCL1-tg splenocytes to wild-type C57BL/6J mice using the small molecule VLA-4 inhibitor firategrast in drinking water...The combination of ibrutinib and idelalisib proved to be the most efficient in reducing the phosphorylation of BTK, SYK, ERK1/2 and Akt upon IgM activation, compared to the phosphorylation of stimulated cells without inhibition (N = 6, P = 0.0003, 0.0305, 0.0039, 0.0019, respectively)...Using this model, we show that a) BCR stimulation induces both, an increase in VLA-4 affinity as well as avidity (clustering), b) that PI3K is an essential transmitter between BCR and VLA-4, and c) that VLA-4 inhibition alters tumor infiltration patterns in vivo. Synergies of VLA-4 blockage with established therapy options as a possible way of reducing microenvironment-induced resistance development are currently been investigated."

Preclinical • ITGA4 • SYK