JAK3 kinase inhibitors / Novartis, Gilead - LARVOL DELTA

Regulatory Role of JAK-1/TYK2 Signaling on the Pannus Formation: Novel Mechanisms for JAK Inhibitors in Psoriatic Disease (ACR Convergence 2023) - " In cultured FLS we observed that rIL-22 and rIL-9 induced increased phosphorylation of JAK1/TYK2 and JAK1/JAK3 respectively compared to the culture media only, (p< 0.01). JAK/STAT signaling system of T cells and its regulatory role in the pathogenesis of psoriatic disease is well established.This study provides a novel insight about the role for JAK-1 and TYK2 signaling on pannus formation and demonstrates novel therapeutic targets for treatment of psoriatic disease. Figure 1: JAK-1 regulates rIL-9/rIL-22 induced proliferation of FLS. MTT assay results show that rIL-9/rIL-22 induced proliferation of FLS is inhibited by a specific JAK-1 inhibitor (upadacitinib)."

Immunology • Inflammation • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatology • Seronegative Spondyloarthropathies • CXCL8 • IL17A • IL22 • IL23A • IL6 • IL9 • JAK1 • JAK3 • MMP3 • TYK2

Azacytidine Inhibits Megakaryopoiesis Via the Induction of Immunogenic RNA Species and Activation of Type-I Interferon Signaling (ASH 2019) - P3; "Eltrombopag (EP), a second-generation small molecule thrombopoietin receptor (TPO-R) agonist was effective in raising platelet counts in patients with MDS as a single agent, as well as in combination with certain standard of care therapies...Importantly, inhibition of IFN-I signal activation using the JAK3 inhibitor decernotinib, the IFNα/β-blocking peptide, B18R, or RNA interference-mediated knock-down of SOCS1 counteracted the inhibitory effects of AZA on TPO-R stimulation and restored megakaryopoiesis...Findings of our study are consistent with and provide a molecular explanation for the observations made in the context of the SUPPORT study. In the future, it will be critical to better understand and potentially counteract the megakaryopoiesis-inhibitory effects by IFN-I pathway activation upon AZA therapy in patients with MDS/AML."

CD34

Discovery and Characterization of the Topical Soft JAK Inhibitor CEE321 for Atopic Dermatitis. (PubMed, J Med Chem) - "The JAK kinases JAK1, JAK2, JAK3, and TYK2 play key roles in cytokine signaling. Therefore, we consider CEE321 to be a "soft drug". When applied topically to human skin that was stimulated with the cytokines IL4 and IL13 ex vivo, CEE321 potently inhibited biomarkers relevant to atopic dermatitis."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • IL13 • IL4 • JAK1 • JAK2 • JAK3 • TYK2

[VIRTUAL] Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with BRAF V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC). (ASCO 2020) - P2 | "57/62 tumor samples retrieved from 93 pts were centrally confirmed to have BRAF V600E mut; 5 non-confirmed BRAF tumors (3 pts had PR) were positive for c-MET T1010I, KRAS G12V, ALK fusion and 2 JAK3 S493C with mPFS of 13.8 mo while OS was NE due to limited data points. This update of BRF113928 study reported improved and durable OS rates with combination D+T in BRAF V600E mut NSCLC pts. Co-occurring genetic alterations might influence clinical outcomes of such pts. Further validation is ongoing to corroborate current genomic findings."

Clinical • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • ALK • BRAF • IDH1 • JAK3 • KRAS • MET