PROTAC: A Novel Drug Delivery Technology for Targeting Proteins in Cancer Cells

Abstract

The treatment measures of malignant carcinomas are most important for the progress of human health. In recent years the use of targeted therapy based on small molecules compounds and identical immunoglobulin are the most frequently used tools to combat cancerous cells. But there are still several limitations in their clinical development and applications of these technologies comprising their ability to bind multiple molecular target sites including both cell surface receptors and intracellular proteins and therefore promoting greater risk of toxicity. PROTAC a novel technology that work on maintaining balance between protein synthesis and degradation and make use of molecules instead of conventional enzyme inhibitor, containing two active domains and a linker to destroy unwanted selective protein (like kinase, skeleton protein and regulatory protein). PROTACs are the heterobifunctional nano molecules with size range of about 10 nanometres find application to eliminate the protein complexes formed by protein-protein interaction through large and flat surface generally defined as “undruggable” in conventional drug delivery system, which include around 85 % of proteins present in humans, suggesting their wide application in the field of drug development. Such peptide-based PROTACs have shown the destruction of targets in cultured cells successfully (e.g., MetAP-2, and FKBP12F36V, receptors for estrogens and androgen). However, some obstacles prevent this technology from transferring from the laboratory to its actual clinical utility, such as delivery system and bioavailability. The scope of the presented review is to gives an overview of novel PROTAC technology with its limitations, advantages , mechanism of action, development of photo-controlled PROTACs and to summarize its futuristic approach in targeting proteins in cancer cells.

CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon

“…We note that BETp are currently not ready for clinical use (37), and furthermore, although there was no significant difference in body weight changes, the combination was on a downward trend (Figure 7D), suggesting room for improving the drug formulation, dosing, and/or schedule. Nevertheless, our results provide a critical proof of concept for dual-pathway targeting and anticipate improvements to both inhibitor classes.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…cIAP1, cIAP2, and X‐chromosome‐linked IAP (XIAP) belong to the family of antiapoptotic proteins that play a critical role in the control of apoptotic machinery 354–361 . The widespread use of IAPs as an E3 ligase in TPD has drawn much attention from scientists in both academia and industry 362–368 . Correspondingly, many IAPs inhibitors were discovered and applied in the design of PROTAC degraders 284 .…”

“… 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 The widespread use of IAPs as an E3 ligase in TPD has drawn much attention from scientists in both academia and industry. 362 , 363 , 364 , 365 , 366 , 367 , 368 Correspondingly, many IAPs inhibitors were discovered and applied in the design of PROTAC degraders. 284 Specifically, the pink moiety is exposed to the solvent as a potentially ideal linking position in the design of PROTAC degraders, based on the crystal structure of IAPs inhibitor with IAPs protein (Figure 5 ; PDB ID: 5M6H).…”