MRC37

MRC37 is a high-affinity TRIM21 ligand with a K d of 0.4 µM. MRC37 targets the IgG Fc-binding pocket in the PRYSPRY domain of TRIM21, mimics the "HHNY" epitope, and inhibits substrate-induced aggregation and activation of TRIM21 via competitive blockade of antibody binding. MRC37 effectively blocks TRIM21 -mediated antiviral immunity (such as adenovirus neutralization) and Trim-Away targeted protein degradation without cytotoxicity. MRC37 antagonizes TRIMTAC activity, and its multiple modification sites do not affect target binding, making it suitable as a degrader warhead for research on viral immunity and neurodegenerative diseases such as tauopathies ^[1].

In Vitro, MRC37 (0.4 μM; 48 h) binds to purified TRIM21 PRYSPRY domain with high affinity (0.4 μM) and exhibits no TRIM21-dependent cytotoxicity in wild-type RPE-1 cells at concentrations up to 20 μM for 48 h^[1]. MRC37 (1 μM) monovalent ligand does not drive ternary complex formation between TRIM21 and H2B-mEGFP-Halo in RPE-1 cells, nor does it affect TRIM21 PRYSPRY binding when modified to generate TRIMTAC derivatives^[1]. MRC37 (0.01-100 μM; 48 h) does not induce degradation of monomeric mEGFP-Halo, oligomeric CAV1-mEGFP-Halo, or oligomeric Cavin1-mEGFP-Halo in RPE-1 cells at concentrations up to 100 μM for 48 h^[1]. MRC37 (50-100 μM; 15 h) inhibits TRIM21-mediated antiviral activity in HEK293T cells and TRIM21-dependent protein degradation in RPE-1 cells in a dose-dependent manner^[1]. MRC37 (5 μM) does not degrade oligomeric Myd88 Myddosomes in stimulated cells, but can compete with TRIMTAC MRC414 to partially reverse inhibition of seeded tau aggregation in HEK293 reporter cells^[1].

References:
[1]. Luptak J, et al. State-selective small molecule degraders that preferentially remove aggregates and oligomers. Nature communications. 2025 Nov 25;16(1):10486.