The advent of PROTAC has brought solutions to targets that traditional small-molecule drugs cannot be made into. After 2017, PROTAC technology has developed rapidly, from the laboratory to the industrial world, starting from Harvard University, Yale University, Arvinas, C4, Kymera Therapeutics have been established to specialize in PROTAC technical drug research, and received about 2 billion US dollars in funding. Drug development giants have joined the ranks, including Pfizer, Roche, GSK, Merck, Novartis, Merck, AbbVie, Gilead, Bristol-Myers Squibb, etc.
Medicilon’s PROTAC drug discovery technology platform summarizes the currently popular and popular target protein ligands; has established a wide range of popular target proteins with high affinity small molecules and small molecule fragment compound libraries (TPSM), and a wide range of E3 ligases with high affinity Small molecules and small molecule fragments (E3SM); a linker system has been established, including the collection of a large number of bifunctional linkers (BF-Linker) with wide diversity. These accumulated compound libraries can help quickly and efficiently synthesize a large number of highly active PTROTAC bispecific small molecules, which greatly improves the drug development process using PROTAC technology. In addition to rapid synthesis, we also established and perfected the PROTAC biological screening and testing platform, and followed up to all pre-clinical stages.
But PROTAC cannot solve all target problems. For example, the target of PROTAC is usually intracellular proteins, but it can’t do anything about secreted proteins and cell membrane proteins. The degradation of cell membrane proteins is usually done through the lysosomal pathway, such as the EGFR degradation process caused by EGF. Therefore, the lysosomal degradation pathway has also become the main design idea for targeted degradation of membrane proteins.
On July 29, in a study recently published in the journal Nature, a team of scientists from Stanford University reported on a different protein degradation technology-lysosome-targeting chimaeras (LYTACs), It opens up new possibilities for targeted degradation of extracellular and membrane-bound proteins.
Lysosome-targeting receptors (LTRs) on the cell surface mediate the transport of proteins to lysosomes and subsequent degradation processes. Based on this, the author designed the LYTAC system to target the degradation of secreted proteins and extracellular proteins.
The LYTAC system consists of two main parts. One part is the specific antibody corresponding to the substrate protein to be degraded, which can specifically bind to the substrate protein to be degraded; the other part is the NCA polymer containing M6P branch that can bind to the LTR. Glycopeptide (n=20~90), to ensure that the substrate protein at the other end can enter the lysosome along with the LTR and then complete the degradation. In the experiment, the researchers also proved and optimized the two functions of LYTAC.
First, the researchers connected the fluorescent molecule NA-647 to the BCA glycan peptide, and detected that M6P and M6Pn can effectively carry the cargo into the cell and localize it to the lysosome; then, the researchers connected the mouse to the M6P polymer Using two different substrate proteins and protein antibodies to test the ability of the conjugate transporter, the results proved that different kinds of proteins were transported into the cell, indicating the universality of LYTAC for different proteins.
The researchers further selected EGFR, PD-L1 and CD71 as examples to prove that the substrate protein can be successfully degraded by lysosomes after being successfully transported into the cell by LYTAC. Based on the clinically used EGFR monoclonal antibody cetuximab, the experimenters synthesized the second LYTAC molecule-Ab-2, and found that Ab-2 can effectively degrade the EGFR molecule, and this process relies on IGFR2 and can be high. The concentration of M6P competitive inhibition can also be blocked by the lysosomal inhibitor chloroquine.
More importantly, through proteomics testing, researchers found that Ab-2 has extremely strong specificity, only degrading EGFR protein without off-target effects; using anti-PD-L1 antibody and another PD-L1 antibody atezolizumab as Basically, the author synthesized a third LYTAC molecule-Ab-3 and Atz-M6Pn, and found that both LYTAC can degrade PD-L1 molecule.
So far, the researchers fully proved the feasibility and effectiveness of LYTAC to degrade protein. This is a very interesting complement to the function of PROTAC, an extracellular domain that binds proteins, and an intracellular domain that binds proteins. At the same time, as a newly discovered method for preparing medicines, LYTAC still has many shortcomings that need to be improved, but overall, LYTACs as an effective tool that can expand the range of degradable proteins have very promising prospects. Medicilon will also continue to pay attention to the progress of this new method, hoping to help further reveal the synthesis, pharmacokinetics, and toxicological properties of LYTACs.
Medicilon (stock code: 688202) was established in 2004 and is headquartered in Shanghai. It is committed to providing a full range of preclinical new drug research services for global pharmaceutical companies, research institutions and scientific researchers. Medicilon’s one-stop comprehensive service helps customers accelerate the development of new drugs with strong project management and more efficient and cost-effective R&D services. The services cover the entire process of pre-clinical new drug research in medicine, including drug discovery, pharmaceutical research and clinical trials. Pre-research. Medicilon grows together with high-quality customers at home and abroad, and provides new drug research and development services to more than 700 customers around the world. Medicilon will continue to base itself on a global perspective, focus on innovation in China, and contribute to human health!
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