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 Nrf2 inhibitor in tumor therapy / 药学学报

Nrf2 is a multi-effect transcription factor, which plays a crucial role in cytoprotective system. With the deepening of research on new regulatory modes and biologic functions of Nrf2, the oncogenic role of Nrf2 in malignant transformed tumors is increasingly obvious. More and more evidences show that Nrf2 is involved in the whole process of tumor occurrence, development, metastasis and prognosis, and inhibiting Nrf2 may be a promising strategy in tumor therapy. However, the development of Nrf2 inhibitors is still in early stage. In this paper, the biological function of Nrf2 and its dual role in tumor are briefly introduced, and representative Nrf2 inhibitors are reviewed according to their structure types, so as to provide reference and ideas for the development of anti-tumor drugs centering on the regulation of Nrf2.

Advances in anti-tumor drug research based on reactive oxygen regulation / 药学学报

Reactive oxygen species (ROS) which were partial metabolites of oxygen are highly reactive. Different concentrations of ROS have different effects on tumor development. Tumor cells have a high level of reactive oxygen species. The antioxidant system of tumor is in highly activated state, and thus modulation of reactive oxygen species levels could be an effective strategy to target cancer cells. Treatment with small molecules that disrupt the redox balance can kill tumor cells first. This paper outlines the main ideas of developing anti-tumor drugs based on reactive oxygen species regulation, and summarizes the representative drugs and research progress according to the mechanism of action, in an effort to suggest potential reference and ideas for developing anti-tumor drugs based on reactive oxygen species regulation.

First-in-class small molecule drugs in 2018 / 药学学报

In 2018, FDA approved 59 kinds of new drugs in all, breaking the record of 53 set in 1993. There were 34 types of small molecule drugs, which accounted for 64% of the whole new drugs. Of these 34 new small molecule drugs, 9 first-in-class ones marked a milestone for the subsequent drug discovery and development. These include Glasdegib, the world's first small molecule inhibitor targeting Smo through Hedgehog signaling pathway; Ivosidenib, the first small molecule inhibitor targeting mutant IDH1; Tecovirimat, the first small molecule drug for anti-variola virus therapy through targeting p37; Baloxavir marboxil, the first anti-flu drug targeting cap-dependent endonuclease; Elagolix sodium, the first small molecule inhibitor in treating endometriosis by targeting GnRH-R, etc. The research and development of first-in-class drugs is always full of obstacles and challenges. However, once they were successfully recognized as the "heavy bomb" drugs, they would become huge benefits. This article chose the representative first-in-class small molecule drugs that were approved in 2018 as examples to analyze their development processes in an attempt to provide guidance for the research and development of more first-in-class drugs.

Protein degradation as an innovative strategy in drug discovery / 药学学报

The success rate of mechanism-based drug discovery depends on the drug targets. With the rapid development of genomics and proteomics, a lot of nonenzymic proteins have been identified as potential drug targets. However, these nonenzymic proteins cannot be regulated by occupying the active site, which were recognized as undruggable targets. Direct regulation of the concentration of these proteins in cells by the innate ubiquitin-proteasome is a potential approach to target these proteins. The ubiquitination of target protein by E3 ligase is the key step for ubiquitin-proteasome mediated protein degradation. Proteolysis targeting chimeras (PROTACs) can facilitate the assembly of complex that consists of the target protein and E3 ligase. The target protein will be ubiquitinated, leading to the degradation by proteasome. This type of regulation mechanism can expand the scope of potential drug targets, and the development of PROTACs may be an innovative strategy in drug discovery.