Research progress and potential medical applications of anaplastic lymphoma kinase in treatment of non-small cell lung cancer / 中国药理学通报

During the treatment of non-small cell lung cancer ( NSCLC) , many patients have developed drug resistance due to the use of targeted EGFR inhibitors. The main reasons for drug resistance are EGFR site mutations and bypass activation. Activation of ALK pathway is one of the major types of bypass activation. A recent authoritative study indicates that ALK is closely related to immunotherapy. This article reviews the treatment of ALK in tumors from three aspects: the structure and physiological function of ALK, the small molecule inhibitor of ALK, the biological function of ALK and its related treatment methods for NSCLC, and prospects future directions for better application of ALK in the treatment of NSCLC.

Research progress in controllable proteolysis targeting chimeras / 药学学报

Proteolysis targeting chimeras (PROTACs) is an innovative technique in targeted protein degradation. PROTACs is a heterobifunctional molecule which can bind to the E3 ligase and target protein to form a ubiquitination complex, resulting in the ubiquitin-proteasome system dependent degradation of target protein. PROTACs has been regarded as the promising method in drug discovery campaign, for its high commonality, potent degradation activity and unique selectivity profile. However, the catalytic mechanism also induces the uncontrollable protein degradation risk. Controllable PROTACs contain the responsive element in the molecular entity. In certain conditions, the element can be triggered to activate or terminate the degradation event. In this review, we will briefly summarize the strategies in controllable PROTACs and describe the representative examples according to the responsive mechanism. We hope this review could provide some insight into the further development of controllable PROTACs.

Research progress of targeted degradation of Mycobacterium tuberculosis proteins / 药学学报

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), is still one of the significant threats to human life. In recent years, the continuous exploration of small molecule inhibitors represented by bedaquinoline has brought new vitality into the field of tuberculosis. However, small molecule inhibitors will inevitably occur acquired drug resistance during clinical medication. As a new pharmacological mechanism, targeted protein degradation (TPD) achieves efficacy by destroying rather than inhibiting protein targets. It might be an excellent strategy to develop anti-tuberculosis drugs based on the TPD concept to solve drug resistance. This article reviews the protein degradation pathways of Mtb, such as the Pup proteasome system and the ClpP-ClpC1 complex enzyme system. The future development of these strategies into TPD drugs was prospected and summarized.

Advances and prospects in targeted protein degradation / 药学实践杂志

Targeted protein degradation (TPD) techniques eliminate pathogenic proteins by hijacking the intracellular proteolysis machinery which includes the ubiquitin-proteasome system (UPS) and the lysosomal degradation pathway, holding promise to overcome the limitations of traditional inhibitors and further broaden the target space including many “undruggable” targets, and provide new targeted treatments for drug discovery. In this review, recent advances in a variety of promising TPD strategies were summarized, such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting chimera AUTAC and AUTOTAC, particularly. The representative case studies, potential applications and challenges were analyzed.

Research advances in new technologies in targeted protein degradation / 药学学报

In recent years, the targeted protein degradation technology has developed quickly, with proteolysis-targeting chimera (PROTAC) as the best-known strategy through exploring the ubiquitin-proteasome system. A number of new targeted protein degradation strategies have been emerging to expand the scope of protein degradation technology, including lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs) and chimeras based on chaperone-mediated autophagy (CMA). The emerging methodologies have explored another important protein degradation system in eukaryotes-lysosomal systems, such as the endosome-lysosome pathway and the autophagy-lysosome pathway. This review summaries the mechanisms and features of different strategies for targeted protein degradation, with a special emphasis on the new targeted protein degradation technologies, such as their current status, advantages and limitations.