靶向难成药蛋白——蛋白质降解剂的力量

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical significance.According to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods.In recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets.Among them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets.This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells.This new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets.Finally,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.

Discovery of small molecule degraders for modulating cell cycle

The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corresponding cyclins are major proteins that regulate the cell cycle.In contrast to inhibition,a new approach called proteolysis-targeting chimeras(PROTACs)and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins,achieving targeted degradation.The field of PROTACs and molecular glues has developed rapidly in recent years.In this article,we aim to summarize the latest developments of CDKs and cyclin protein degraders.The selectivity,application,validation and the current state of each CDK degrader will be overviewed.Additionally,possible methods are discussed for the development of degraders for CDK members that still lack them.Overall,this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders,which will be helpful for researchers working on this topic.