Explore Alternative Therapeutics of Hepatocellular Carcinoma Through Proteolysis Targeting Chimeric

Liver cancer is one of the five most common malignancies in the world, whose incidence rate is 5th in male malignant tumors, the 2nd leading cause of death, and 7th in female malignant tumors, the 6th leading cause of death. Hepatocellular carcinoma (HCC) is the main histological type of liver cancer, of which the main treatment methods include surgical resection, liver transplantation, local ablation, TACE, etc. In the past 50 years, despite that the drug treatment of HCC has undergone clinical trials, yet few achieved satisfactory results.

UPS OverviewUbiquitin proteasome system (UPS) is an ATP dependent non-lysosomal protein degradation system that can degrade 80% ~ 90% of the proteins in cells, including cell cycle regulators, tumor suppressors, transcriptional activators and suppressors, cell surface receptors, mutant or damaged proteins, etc. UPS gets involved in the regulation of cell cycle, inhibition or promotion of apoptosis, expression of activating transcription factors and so on, once whose enzymes or motifs recognizing specific substrates undergo functional mutations, the loss of ability to regulate the target proteins can cause cancer protein aggregation, abnormal degradation of tumor suppressor proteins, blocked apoptosis and accelerated proliferation of mutated cells, thus leading to the occurrence of tumors. Therefore, the development of anti-tumor drugs targeting such tumor proteins relying on UPS (e.g. Proteolysis Targeting Chimeric, PROTAC) has great prospects.

UPS Components & ProspectsUPS consists of ubiquitin (Ub), ubiquitin activating enzyme (E1), ubiquitin binding enzyme (E2), ubiquitin ligase enzyme (E3) and 26S proteasome, among which the ubiquitin is a highly conserved polypeptide chain composed of 76 amino acids whose main function is to mark proteins that need to be degraded. E3, a key regulatory enzyme in ubiquitination process, can specifically recognize and bind target proteins, which determines the high specificity and selectivity of UPS.

The E3 enzymes were divided into the HECT family and the RING family according to their different ways of connecting Ub and substrate. The former is mainly connected in the form of sulfur lipid intermediates, while the latter is connected by allosteric mechanism. At present, E3 enzymes related to HCC include IAP, MDM2, SIAH1, SCF, etc. IAP includes c IAP-1, c IAP-2, NAIP, XIAP, survivin and some important molecules regulating apoptosis protease. Survivin, XIAP and Livin/AM-IAP are highly expressed in hepatocellular carcinoma (HCC), and their expression is related to the prognosis of patients. IAP inhibitors can inhibit the binding of IAP to apoptotic protease or deactivate IAP. Smac is considered to be the most characteristic IAP inhibitor, which can induce the apoptosis of XIAP in HCC cells.

PROTAC OverviewPROTAC, a heterobifunctional small molecule made up of a linker and two warheads—one binds to the target protein, and the other recruits the E3 ligase, engages the body's housekeeping protein degradation system (UPS) to selectively degrade the pathogenic proteins. As a novel and promising area of drug discovery, it has the following advantages.

*Degrading pathogenic proteins rather than inhibiting them*Low dosage*Cutting down toxicity*Targeting undruggable proteins*Prolonged pharmacodynamics effect

Biotechnology outsourcing service companies provide PROTAC molecular design services for ubiquitin, PROTAC molecular design services for ubiquitin, including ligand design for target protein, ligand screening for E3 ligase, linker design and optimization, PROTAC structural modification, custom peptide and compound synthesis, etc., to help solve technical problems regarding PROTAC discovery. Ready-to-use linkers, ligands, E3 ligase and target proteins are available to guarantee quick solution to possible obstacles that may hinder any research process.

The abnormal pathways of UPS will lead to abnormal accumulation of proteins in vivo, which will lead to a variety of diseases. This mechanism affords an opportunity for the novel and innovative approach PROTAC to play a big role to help return normal physiological tissue, by locking, ubiquitination and degradation of disease-causing proteins. Associated drug discovery projects are worthy of attention and support, which are hopeful to offer therapeutic interventions beyond the limitations of current existing approaches targeting diseases of human systems & organs: nervous system (Parkinson's disease, PD, Alzheimer's disease, AD), immune system, heart, liver, kidney and others.

ReferenceBERNASSOLA F, KARIN M, CIECHANOVER A, et al. The HECT family of E3 ubiquitin ligases: multiple players in cancer development[J]. Cancer Cell, 2008, 14 (1) :10-21.

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