RAF709 / Novartis - LARVOL DELTA

Korean red ginseng extract suppresses food allergy by remodeling the gut microbiota and restoring immune homeostasis in IL4raF709 mice. (PubMed, J Ginseng Res) - "In contrast, Oscillospiraceae (Eubacterium_g8, Acetobacter, and Pseudoflavonifractor) was associated with allergy exacerbation. KRGE mitigates FA in IL4raF709 mice by restoring gut microbiota balance and immune homeostasis, suggesting its potential as a microbiota-targeted intervention for FA."

Journal • Preclinical • Allergy • Food Hypersensitivity • Immunology • Infectious Disease • CDK1 • IL13 • IL33 • IL4R • ITGAE • ITGAM

Induction of Immune Tolerance in a Food Allergy Model Utilizing Platelet-Targeted Therapy (ASGCT 2025) - " Using ovalbumin (OVA) as a model allergen, we investigated two mouse models: the OVA-specific OT-II model (98% OVA-specific CD4 T cells) and IL4raF709 mutant mice (prone to allergic responses)... Our findings demonstrate that platelet-targeted gene therapy induces immune tolerance by modulating the Th2/IgE pathway and preventing anaphylaxis. Furthermore, transfusion of allergen-expressing platelets mitigates anaphylactic responses, with suppression of mast cell activation, highlighting a novel therapeutic approach for food allergy treatment. Disease Focus of Abstract:Other Other: Food allergy"

Allergy • Food Hypersensitivity • Gene Therapies • Hematological Disorders • Hemophilia • Immunology • Infectious Disease • Rare Diseases • CD4 • IL4R

Utilizing Platelet-Targeted Gene Therapy to Induce Immune Tolerance in Food Allergy (ASGCT 2024) - "PCR analysis showed that 2bOVA proviral DNA was detected in all 2bOVA-transduced recipients. Average platelet-OVA expression levels were 11.49 ± 7.49 ng/108 platelets in 2bOVA-transduced OT-II HSCs in wild-type recipients (the OT-II model) and 6.82 ± 6.89 ng/108 platelets in 2bOVA-transduced IL4raF709 recipients (the IL4raF709 model). After the OVA challenge, within 20 min, the body temperature dropped 1.89 ± 1.29 ºC and 2.05 ± 0.59 ºC in the 2bGFP-transduced control mice in the OT-II model and the IL4raF709 model, respectively, but did not change in the 2bOVA-transduced animals."

Gene therapy • Allergy • Bone Marrow Transplantation • Food Hypersensitivity • Gene Therapies • Hematological Disorders • Hemophilia • Immunology • Infectious Disease • Rare Diseases • Transplantation • CD4 • IL4R

BRAFi-induced ROCK-mediated non-canonical nuclear β-catenin shuttling drives a phenotypic switch in cancer-associated fibroblasts. (AACR 2024) - "Here, we present compelling evidence showing that BRAFi (PLX4032), but not CRAF inhibitor (GW5074) or pan-RAF inhibitor (RAF709), induces the accumulation of nuclear β-catenin in CAFs harboring wild-type BRAF, a process mediated by BRAF and CRAF but not ARAF isoform. In summary, BRAFi reprograms the transcriptional activity in CAFs by driving increased nuclear β-catenin to increase their ability to remodel the tumor ECM and promote melanoma cell proliferation. Collectively, the data offer new insights into the molecular mechanisms that underlie the paradoxical reprogramming of CAFs by BRAFi in melanoma therapy through the non-canonical β-catenin pathway."

Melanoma • Oncology • Solid Tumor • ARAF • CAFs • CTNNB1

RAF1 mediates the FSH signaling pathway as a downstream molecule to stimulate estradiol synthesis and secretion in mouse ovarian granulosa cells. (PubMed, Ann Transl Med) - "The process is blocked by treating granulosa cells (GCs) with the RAF1 inhibitor, RAF709...Our in vitro and in vivo studies clearly illustrate RAF1 plays an important medium adjusting role in the FSH signaling pathway, and RAF1 acting as a downstream molecule to trigger ERK phosphorylation to stimulate GC E2 synthesis and secretion. RAF1 plays a pivotal mediating role in the FSH signaling pathway by inducing the phosphorylation of ERK and promoting E2 synthesis."

Journal • Preclinical • Hematological Malignancies • Leukemia • Oncology • CYP19A1 • RAF1

Design and Discovery of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (LXH254)- A selective, efficacious and well-tolerated RAF inhibitor targeting RAS mutant cancers: The path to the clinic. (PubMed, J Med Chem) - "Herein, we describe 15 (LXH254, Aversa, R.; et al...Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al...Further mitigation of human intrinsic clearance and TDI led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials."

Journal • Addiction (Opioid and Alcohol) • Oncology