BRD5529 is a Selective CARD9–TRIM62 PPI Inhibitor

The allele family CARD9 variant relates to increased or protected risk of inflammatory bowel disease (IBD). Moreover, the susceptible variant of CARD9 is related to the increase of NF-κ B-mediated cytokine production. In contrast, the protective variant lacks a functional C-terminal domain and cannot raise E3 ubiquitin ligase trim62. Meanwhile, CARD9 plays a key role in mediating innate immune signals of C-type lectin receptors such as Dectin-1 and mingle. These receptors are responsible for identifying bone marrow cells in fungi and mycobacteria. Although the protective variant CARD9 Δ 11 has a complete N-terminal sequence, it lacks activity and has a major negative impact on CBM signal transmission. E3 ubiquitin ligase trim62 interacted specifically with the WT CARD9 C-terminal domain (CTD) and activated CARD9 by K27 ubiquitination. BRD5529 is a selective CARD9-E3 ubiquitin ligase TRIM62 protein-protein interaction inhibitor.

BRD5529 is a selective CARD9-E3 ubiquitin ligase TRIM62 protein-protein interaction inhibitor with an IC50 of 8.6 μM. Specifically, BRD5529 directly and selectively binds CARD9, disrupts TRIM62 recruitment, inhibits TRIM62-mediated ubiquitinylation and activation of CARD9. Moreover, BRD5529 demonstrates cellular activity and selectivity in CARD9-dependent pathways. Furthermore, BRD5529 significantly reduced IKK phosphorylation in the context of Dectin-1 activation (scleroglucan treatment). But IKK phosphorylation was not affected upon LPS-triggered CARD9-independent TLR4 activation. BRD5529 produced dose-dependent inhibition of TRIM62-mediated CARD9 ubiquitinylation in vitro. Still, BRD5529 functions in a CARD9-specific manner. In addition, BRD5529 attenuated activation of the NF-κB reporter in THP-1 monocytes treated with scleroglucan or whole glucan particles (WGPs). But it had no effect on LPS-driven CARD9-independent NF-κB activation. All in all, BRD5529 is a selective CARD9-E3 ubiquitin ligase TRIM62 protein-protein interaction inhibitor.


Leshchiner ES, et al. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11392-11397.