Targeted inhibition of the COP9 signalosome for treatment of cancer

Abstract

The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin–proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

“…Jab1 is a tumour oncogene in a variety of human cancers 46,47 and has been shown to be a key molecule in nicotine-induced lung cancer. 48,49 Remarkably, Csn5/Jab1 mediates stabilization of PD-L1, which is crucial for breast cancer cells to escape immune surveillance via PD-L1/PD-1 interaction. Immune checkpoint-blockade treatments targeting PD-1/PD-L1 have revolutionized various cancers therapy.…”

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

“…Next Dr. Eva Altmann (Novartis) reported on targeting cullin‐RING E3 ligase with inhibitors focusing on constitutive photomorphogenesis 9 (COP9) signalosome subunit 5. COP9 prevents the degradation of the cullin‐RING E3 ligase and therefore upregulates the degradation of cullin‐RING E3 ligase, functioning as a tumor suppressor . Finally, Prof. Dr. Michael Groll (TU München) presented his research on proteasome inhibitors using screening based on structural and mass spectrometry analyses, revealing a novel reaction mechanism involving polarity inversion and irreversible crosslinking of the proteasomal active site.…”

“…COP9 prevents the degradation of the cullin-RING E3 ligase and therefore upregulates the degradation of cullin-RING E3 ligase,f unctioning as at umor suppressor. [28] Finally, Prof. Dr.M ichael Groll (TU München) presented his research on proteasome inhibitors using screening based on structurala nd mass spectrometry analyses,r evealing an ovel reaction mechanism involvingp olarity inversion and irreversible crosslinking of the proteasomal active site. The group identified the sulfonyl head group for the development and optimization of immunoproteasome-selective compounds.…”

Knockdown of COPS3 inhibits the progress of prostate cancer through reducing phosphorylated p38 MAPK expression and impairs the epithelial‐mesenchymal transition process

“…Therefore, CSN may become a platform of signaling proteins proteolysis and is critical for organisms’ growth and development. It is not surprising that CSN is linked with multiple cancers; however, the mechanistic regulation of its each subunit has still not been identified …”