Recently, Professor Li Minyong’s team from the School of Pharmaceutical Sciences, Shandong University made new progress in the field of targeted protein degradation and published a research paper entitled “Targeted Protein Degradation Induced by HEMTACs Based on HSP90” in Journal of Medicinal Chemistry (IF = 8.039, Top). Professor Li Minyong is the corresponding author. PhD candidate Li Zhenzhen is the first author. Shandong University is the sole first and corresponding author institute.

In the process of continuous exploration of new drugs, researchers are developing new strategies to target disease-associated proteins. Conventional small-molecule inhibitors are bound to the protein of interest to block receptor agonist-mediated effects. However, 80% of disease-related proteins cannot be targeted by small molecules, which are called "undruggable". Therefore， different ways need to be developed to prevent disease-related proteins from functioning. Targeted protein degradation induced by small molecules is the most noteworthy in recent years. Targeted protein degradation strategies open up new avenues for therapeutics and provide powerful tools for biological inquiry. The emergence of novel degradation technologies has the potential to overcome the limitations of small-molecule inhibitors. However, some of these degradation technologies may cause promiscuous degradation of POI in many tissues and organs, not involved in the disease process, resulting in undesirable side effects during treatment. Small-molecule PROTACs, on the other hand, exert degradation effects via “hijacking” E3 ligases. However, studies have revealed that VHL- and CRBN-based small-molecule PROTACs can cause resistance mechanisms and off-target effects in cells. Therefore, it is critical to broaden the scope of TPD strategies.

Professor Li Minyong's team presents a new approach, termed HEat shock protein 90 (HSP90)-Mediated TArgeting Chimeras (HEMTACs), to induce intracellular protein degradation by bridging a target protein to HSP90 to drive the downregulation of proteins. They successfully showcase HEMTACs for cyclin-dependent kinase 4 and 6 (CDK4/6) by using a flexible linker to connect the targeting warhead of CDK4/6 with the HSP90 ligand. On the other hand, compared with normal tissues, the HSP90 chaperone complex is overexpressed and hyperactivated in tumor tissues, which leads to the unique tumor-selective pharmacokinetics of small molecules that bind to HSP90, such as HEMTACs, which could exploit the tissue specificity of HSP90 and target proteins to drive selective degradation of target proteins in specific cell types, tissue types and disease states. In addition, the tissue- or cell-type specificity of HSP90 also opens the possibility of developing HEMTACs against ubiquitously expressed target proteins, which has the potential to improve the therapeutic index.

Overall, the development of HEMTACs as a whole broadens the scope of TPD and has the potential to provide therapeutic interventions that are currently unavailable. These findings also underscore the value of incorporating HSP90 into TPD design to expand the scope of TPD strategies that mediate ligand-induced protein degradation.

This work was supported by grants from the National Natural Science Foundation of China, the Taishan Scholar Program at Shandong Province, the Shandong Natural Science Foundation and the Foundation for Innovative Research Groups of State Key Laboratory of Microbial Technology.

Link to the article:https://doi.org/10.1021/acs.jmedchem.2c01648