Targeting Cullin-RING E3 Ligases for Radiosensitization: From NEDDylation Inhibition to PROTACs

Abstract

As a dynamic regulator for short-lived protein degradation and turnover, the ubiquitin-proteasome system (UPS) plays important roles in various biological processes, including response to cellular stress, regulation of cell cycle progression, and carcinogenesis. Over the past decade, research on targeting the cullin-RING (really interesting new gene) E3 ligases (CRLs) in the UPS has gained great momentum with the entry of late-phase clinical trials of its novel inhibitors MLN4924 (pevonedistat) and TAS4464. Several preclinical studies have demonstrated the efficacy of MLN4924 as a radiosensitizer, mainly due to its unique cytotoxic properties, including induction of DNA damage response, cell cycle checkpoints dysregulation, and inhibition of NF-κB and mTOR pathways. Recently, the PROteolysis TArgeting Chimeras (PROTACs) technology was developed to recruit the target proteins for CRL-mediated polyubiquitination, overcoming the resistance that develops inevitably with traditional targeted therapies. First-in-class cell-permeable PROTACs against critical radioresistance conferring proteins, including the epidermal growth factor receptor (EGFR), androgen receptor (AR) and estrogen receptor (ER), cyclin-dependent kinases (CDKs), MAP kinase kinase 1 (MEK1), and MEK2, have emerged in the past 5 years. In this review article, we will summarize the most important research findings of targeting CRLs for radiosensitization.

Celecoxib Synergistically Enhances MLN4924-Induced Cytotoxicity and EMT Inhibition Via AKT and ERK Pathways in Human Urothelial Carcinoma

“…It targets intracellular peptides that are produced by the proteasome 30 . MLN4924 is a selective NAE1 inhibitor identified as a novel anticancer agent by triggering cell apoptosis, senescence, autophagy, and chemosensitization/radiosensitization 31 , 32 , which has a similar effect as bortezomib; it selectively blocks the protein degradation regulated by CRL E3 ligases and produces limited cytotoxicity. However, compared with MLN4924, bortezomib blocks all the protein degradation through the 26S proteasome and thus offers higher cytotoxicity 8 .…”

Advances in molecular targeted therapies to increase efficacy of (chemo)radiation therapy

“…In contrast to "conventional" targeted therapies employing small molecules to inhibit enzymatic function by competitive inhibition of druggable active sites, this technology degrades the POI, abolishing not only its enzymatic activity but also possibly circumventing some protein-intrinsic resistance mechanisms, such as activating mutations [150,152]. PROTACs offer great potential to overcome the RT resistance of tumor cells by targeting, for example, receptors like EGFR, androgen (AR) and estrogen receptor (ER), or kinases, including CDKs and mitogen-activated protein kinase 1/2 (MEK ½; reviewed in [153]). Promising data for the development of PROTACs to sensitize tumors in vivo have further been acquired in a xenograft model using the FDA-approved AR degradation enhancer ASC-J9, showing significant effects in prostate cancer [154].…”

Manifold role of ubiquitin in Helicobacter pylori infection and gastric cancer

“…Recent advances in the ubiquitinylation field have allowed the development of cell-permeable molecules called Proteolysis Targeting Chimeras (PROTACs) for selective targeting of different proteins by linking them to an E3 ubiquitin ligase for degradative ubiquitination [ 162 , 163 ]. A PROTAC for MDM2, for example, consists of a nutlin-based MDM2 ligand joined to the E3 ubiquitin ligase cereblon (CRBN; CRL4 CRBN ) via a short linker and promotes efficient degradation of MDM2 in leukemia cells [ 164 , 165 ].…”

“…A PROTAC for MDM2, for example, consists of a nutlin-based MDM2 ligand joined to the E3 ubiquitin ligase cereblon (CRBN; CRL4 CRBN ) via a short linker and promotes efficient degradation of MDM2 in leukemia cells [ 164 , 165 ]. The E3 ubiquitin ligases SCF β−TRCP , CRL2 VHL , IAPs and MDM2 are tools in this promising technology to target proteins, which confer inflammatory effects, tumorigenesis and radiotherapy resistance (such as histone deacetylases, androgen and estrogen receptors, EGFR, and CDKs), for ubiquitin-mediated degradation [ 163 ]. This new protein engineering approach is able to guide the development of advanced therapeutics for different pathologies, including gastric cancer.…”