JMS-175-2 is a specific, small molecule inhibitor Zn2+-dependent JAMM/MPN deubiquitylase (DUB) BRCC36 isopeptidase complex (BRISC) with IC50 of 3.8 uM.
JMS-175-2 does not inhibit AMSH* (a STAM2 AMSH fusion), the nuclear ARISC complex, UPS2, and BRCC36 Abraxas2 complex.
JMS-175-2 inhibits BRISC-mediated cleavage of polyubiquitin chains.
JMS-175-2 acts as molecular glue, stabilises two BRISC octamers to form a BRISC dimer with 16 subunits.
JMS-175-2 (2.5 uM) reduces interferon-stimulated gene (ISG) expression in cells MCF10A Cas9 cells expressing BRCC45 wild-type (WT), and in healthy and SSc PBMCs.
BRCC36 is a JAMM (JAB1, MOV34, and MPR1, Pad1 N-terminal (MPN)) metalloenzyme DUB family and selectively cleaves lysine 63-linked ubiquitin (K63-Ub) chains.
BRCC36 is present in two distinct macromolecular assemblies: a cytoplasmic BRCC36 isopeptidase complex (BRISC), and the nuclear Abraxas1 isopeptidase complex (ARISC).
The BRISC complex regulates Type I interferon signalling by deubiquitylating and stabilising Type I interferon (IFNAR1) receptors, whilst the ARISC complex interacts with the tumour suppressor protein BRCA1 and localises to double-stranded DNA breaks to facilitate DNA damage repair.