PROTAC of magical small molecule drug development technology

Although monoantigen has the advantage of high affinity and high selectivity relative to small molecules, its biggest disadvantage is that it can not pass through the cell membrane, so it can not act on the intracellular targetRNAi can pass through the cell membrane and have strong force on the target, but due to its metabolic instability and off-target effect and other disadvantages, the development process is also difficultHowever, the emergence of PROTAC technology has brought the dawn to the bottleneck of small molecule drugs, it seems that it can perfectly solve the many problems faced by small molecule drugsOn March 13, 2020, DrMa Xingquan, Vice President of The Us-Based Dixie Chemistry Department, shared a wonderful explanation of PROTAC technology with colleagues from all walks of life at the Medi-Si Cloud Lecture Hall, and gave a brief review of DrMa's course:what PROTAC technology isPROTAC is an abbreviation for PROteolysis TArgeting Chimeras, meaning that protein hydrolysis target sylluco, a new branch of degradation protein technologyThe principle of PROTAC technology exclaims the natural intracellular protein degradation processProtein degradation is essential and strictly regulated in the normal life activities of cells, and the process is mainly done through the participation of the ubiquitase systemProteins that need to be decomposed are identified and degraded by proteases by marking e1, E2, and E3 ubiquity connecting enzyme systemsPROTAC molecule is a class of dual functional active compounds with dumbbell-type structures, one active end of the molecule can be closely bound with the target protein and connected to another active end by connecting the link linker to the e3 ubiquinoneThis dual-functional molecule can identify the target protein and E3 ubiquitin connecting enzyme in the body, the target protein and E3 ubiquitin connecting enzyme close, the target protein is ubiquitinized, in the body through the ubiquitin-protein body pathway degradationAfter the target protein is degraded, the PROTAC molecule can be released to participate in the degradation process of the next protein, so this degradation has a catalytic effect, and the low dose of the drug can achieve efficient degradationMedithe's research team established the PROTAC drug discovery technology platform, summarized the current popular target protein ligands, established a wide range of popular target protein high affinity small molecules and small molecular fragment compounds (TPSM), a wide range of E3 connecting enzyme high affinity small molecules and small molecule fragments (E3SM); These accumulated compound banks can help quickly and efficiently synthesize large numbers of highly active PTROTAC bispecific small molecules, greatly improving the drug development process using PROTAC technologyIn addition to rapid synthesis, we have also established and improved the PROTAC bio-screening and testing platform, which has evolved to all stages of preclinical developmentMedici's PROTAC research platform has established technical services with a number of biopharmaceutical companies, and some projects have advanced to the preclinical research phase "Focus on innovation, dedicated service", through continuous innovation and improvement, Medici PROTAC research platform has the ability to further undertake a large number of PROTAC technology research, to provide one-stop research and development services let's take a brief look at the evolution of PROTAC technology
Professor Raymond J Deshaies of the California Institute of Technology and Professor Craig M Crews of Yale University first proposed the proTAC concept in 2001, when they reported on the level of expression of proteins that can be artificially regulated for purpose using a peptide segment connection to small molecules 2004, Crews and Alessio Ciulli and others designed and modified the ligands of VHL (part of the E3 ubiquitin connective enzyme complex CRL2VHL) to obtain a VHL ligand with high affinity, and the binding force with VHL can reach the Namor level using this small molecular ligand , the Crews team reported in 2015 that proTAC molecules of estrogen-related receptor sympathisers alpha (ERR alpha) and RIPK2 could be observed at the cellular level Professor Crews established Arvinas in 2013 and uses the PROTAC platform to build a wide range of protein degradation product candidate pipelines for diseases in various organ systems and tissues, and is a leading company in proTAC molecular development, currently advancing ARV-110 and ARV-471 into Phase I clinical trials three elements of PROTAC research
PROTAC effect must be effective with the target protein and E3 enzyme to form an effective terabolic complex, and this process for PROTAC, first of all, need to successfully through the cell membrane into the cell, the second consideration is how to control the concentration to avoid the drug molecule and target protein and E3 enzyme respectively to form a binary complex (hook effect), and fully consider the target protein and E3 enzyme contact area of charge rejection and stereo structure rejection, it is very important And when the teramar complex is formed, whether it can be effectively degraded, it is necessary to fight against the resynthesis of de-uproscyase and target proteinuals until a certain degree of balance is reached second, the selection of E3 ubiquitin connective enzymes is particularly critical About 600 E3 ubiquitin connecting enzymes are known to regulate the function of proteases, which provides an endless opportunity for protein-targeted treatment Since the entire process of target protein degradation depends on the proximity of ligand-induced induction, the co-positioning of E3 ubiquitin connecting enzymes and target proteins in space-time is critical, and differences in tissue expression, subcellular positioning and regulation can all lead to potential pitfalls and opportunities in addition to the biological differences in the re-use of different connective enzymes, there are some physical and chemical differences between the currently available connective enzymes, how to obtain appropriate physical and chemical properties and absorption, distribution, metabolism and excretion (ADME) characteristics, so that it is sufficient to oral administration and/or even reach the central nervous system is extremely important.