Nemtabrutinib

Nemtabrutinib (ARQ 531) is a reversible non-covalent and orally active inhibitor of Bruton’s Tyrosine Kinase (BTK), with IC₅₀s of 0.85 nM and 0.39 nM for WT-BTK and C481S-BTK, respectively. IC50 & Target:IC50: 0.85 nM (WT-BTK), 0.39 nM (C481S-BTK)^[1]. In Vitro:Nemtabrutinib (ARQ 531) shows strong target inhibition in TMD8 cell line. The IC₅₀ values are 0.85 nM and 0.39 nM for WT-BTK and C481S-BTK, respectively, in biochemical assay. Additionally, Nemtabrutinib also shows strong inhibition of TEK kinases with IC₅₀s of 5.23 nM (BMX), 5.80 nM (TEC), 36.4 nM (TXK). The IC₅₀s of Nemtabrutinib for SRC kinases are 3.86 nM (LCK), 4.22 nM (YES), 9.71 nM (BLK), 18.3 nM (HCK), 18.8 nM (LYNa), 25.9 nM (FGR), 32.2 nM (FYN), 48.0 nM (FRK) and for TRK kinases are 11.7 nM (TrkB), 13.1 nM (TrkA), 19.1 nM (TrkC). Nemtabrutinib inhibits proliferation of diverse types of cell lines (TMD8: GI₅₀=0.13 μM, REC1: GI₅₀=0.18 nM) and shows potency in cell lines that are addict to BCR, Src-family kinase and PI3K/AKT pathways. In Vivo:Nemtabrutinib is efficacious in TMD-8 tumor xenograft model. Nemtabrutinib causes complete tumor regression after 14 days of treatment. Nemtabrutinib is also efficacious in collagen induced arthritis model. Nemtabrutinib demonstrates potent efficacy against arthritis in mouse model. In the BTK driven TMD8 xenograft mouse model, Nemtabrutinib demonstrates excellent anti-tumor activity with durable response. Nemtabrutinib demonstrates in vivo efficacy in a mouse collagen-induced arthritis (CIA) model^[1].