[CAS NO. 2095393-15-8]  Nemtabrutinib (ARQ 531)

ARQ 531 potently inhibited BTK (IC50 = 0.85 nM), the binding potency was accompanied by long residence time (51 min). ARQ 531 selectively inhibits BCR signaling dependent PI3K/AKT/mTOR, Ras/Raf/Erk and Rap-GTPase-Cofilin pathways in TMD8 cells. It potently inhibits proliferation of hematological malignant cell lines both sensitive and resistant to ibrutinib addicted to BCR signaling. Unlike ibrutinib, ARQ 531 suppressed both the upstream activating signals (via inhibition of a select member of Src kinase family) and the downstream signaling pathways (via pAKT and pERK kinases). In GCB-DLBCL cell lines (SUDHL-4 and DOHH-2), ARQ 531 potently suppressed expression of anti-apoptotic c-Myc and BCL6 oncoproteins in a dose dependent fashion, and concomitantly induced apoptotic cleavage of PARP protein.