Is it really that nonselective inhibitors have no future in clinical study

The activation of dentritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (Ang II) can enhance the maturation and activation of DCs. This study found that E1 play an important role in Ang II-induced activation of DCs. Firstly, Ang II stimulation significantly up-regulated E1 expression in DCs. Moreover, Ang II treatment markedly induced phenotypic R547 maturation, the secretion of cytokines and immunostimulatory capacity of DCs. In contrast, inhibition of E1 by a small molecule inhibitor, 4 [4-(5-nitro-furan-2-ylmethylene)-3, 5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR41), markedly attenuated these effect. Mechanistically, PYR41 treatment markedly decreased K63-linked ubiquitination of TRAF6 and NEMO, inhibited proteasomal degradation of IkBa and MKP-1 thereby resulting in activation of NF-kB, ERK1/2 and STAT1 signaling pathways in DCs induced by Ang II.

When I first read this article, I can't believe that someone is interested in ubiquitin-activating enzyme E1 inhibitor and even publish this study in "Immunology". Because we  all know that E1 enzyme AZD1152 is required for all ubiquitin reactions involved in the development of the immune system and many phases of the immune response, including its initiation, propagation and termination. The inactivation of E1 may regulates several pathways including TNF, TLR, NLR, RLR and TCR signaling pathways. However, This study demonstrates a novel role of E1 in Ang II-induced activation of DCs, and inhibition of E1 activity might be a potential therapeutic target for DC-mediated autoimmune diseases.

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S2688 R547 R547 (Ro 4584820) is a potent ATP-competitive inhibitor of CDK1/2/4 with Ki of 2 nM/3 nM/1 nM. It is less potent to CDK7 and GSK3α/β, while inactive to other kinases. Phase 1.

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