ICCB-19 hydrochloride is a TRADD (TNFRSF1A associated via death domain) inhibitor. ICCB-19 hydrochloride binds with N-terminal domain of TRADD (TRADD-N), disrupting its binding to both TRADD-C and TRAF2. ICCB-19 hydrochloride is indirect inhibitor of RIPK1 kinase activity. ICCB-19 hydrochloride effectively induces autophagy and the degradation of long-lived proteins[1].

ICCB-19 inhibits Bortezomib-induced apoptosis and RIPK1-dependent apoptosis (RDA) with an IC50 of about 1 μM[1]. ICCB-19 has no effect on mTOR. ICCB-19 (10 μM) treatment of cells increases the levels of DsRed-FYVE dots and the lipid kinase activity of VPS34[1]. ICCB-19 (10 μM) promotes autophagy via K63-linked ubiquitination of beclin 1 mediated by E3 ubiquitin ligases cIAP1 and cIAP2 and the adaptor TRAF2[1]. ICCB-19 (10 μM) reduces the rapid activation of RIPK1 in complex I induced by TNF. Treatment with ICCB-19 increases recruitment of TRADD, HOIP, and A20, but not RIPK1, to complex I[1].

ICCB-19 reduces inflammatory responses in Tradd-/- mice. ICCB-19 reduces expression of the TNF-induced inflammatory target gene products, NOS and COXII27, and of inflammatory cytokines in cells stimulated with pathogen-associated molecular patterns[1].

[1]. Daichao Xu, et al. Modulating TRADD to restore cellular homeostasis and inhibit apoptosis. Nature. 2020 Nov;587(7832):133-138.

.