NSC-697923 #10473

NSC-697923 is a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Ubc13-Uev1A. NSC-697923 blocked formation of Ubc13 and ubiquitin thioester conjugates, and suppressed constitutive NF-κB activity in diffuse large B cell lymphoma cells. Inhibition of ubiquitin-dependent DNA damage signaling was observed, but not formation of the phosphorylated form of histone variant H2AX, which is consistent with NSC-697923 targeting of nuclear Ubc13 (1). Additional data suggested that NSC-697923 interacted with the Ubc13 active site cysteine (2). UBE2N (Ubc13) is an E2 ubiquitin-conjugating enzyme that catalyzes K63-linked poly-Ub chain formation. UBE2N forms a heterodimer with MMS2 or Uev1A to exert its E2 ligase function (3). NSC-697923 treatment of neuroblastoma cells increased apoptosis and nuclear p53 accumulation, and enhanced tumor suppression (4). NSC-697923 also inhibited caspase-1 enzymatic activity (IC₅₀ = 1.737 μM) and NLRP3 protein expression by suppressing the NF-κB signaling pathway. NSC-697923 inhibited joint swelling and NLRP3 inflammasome activation in an animal model of gouty arthritis (5).