Targeting MDM2-p53 degradation presents a new opportunity for the development of MDM2-p53 inhibitors

Transcription factor p53 plays a key role in the demise of tumor cells, and indulation is one of the main factors in tumor occurrence. MDM2 is one of the strongest apoptosis inhibitors ever found, is a cancer gene closely related to malignant tumors, which can regulate p53's various functions, including directly blocking p53's N-end transcriptional activity domain, promoting p53 from the nucleus to cytoprotein, and as an E3 connective enzyme to make p53 ubibination so that p53 degrades.
existing studies confirm that an important mechanism for p53 indestipse is MDM2 over-expression. Therefore, the interaction between MDM2-p53 proteins (MDM2-p53 inhibitors) using small molecules is an effective strategy to promote tumor apoptosis and treat tumor diseases.the development of existing MDM2-p53 inhibitors is not satisfactory
6 entering the clinical MDM2-p53 inhibitor class representative drugs, including Roche's RG7112, RG738 8; Selofi's MI-77301; Daiichi-Sankyo's S-3032; Novarlor's NVP-CGM097; and Amway's AMG 232. These MDM2-p53 inhibitors have shown some potential for development in tumor therapy.
but in fact, from the overall development situation, the current MDM2-p53 inhibitor class of anti-tumor drugs do not have a rapid and successful market of drugs. From the existing research and development, MDM2-p53 inhibitors still have many problems, including: dose is limited by hematology and related toxicity, adverse reactions include neusophilic cell reduction, thermostacyte reduction, long-term cell reduction and bone marrow failure, as well as gastrointestinal toxicity. As a result, researchers are also looking for more effective MDM2-p53 inhibitors to overcome these problems.Targeting MDM2-p53 Degradationbrings new opportunities for the development of MDM2-p53 inhibitors
In recent years, various anti-tumor drug development strategies have developed rapidly, and PROTAC (Protein Degradation Target Chilayer) is one of the emerging cancer drug development strategies.
is different from conventional protein inhibitors in that PROTAC (Protein Degradation Target Chiliosome) is a dual-functional hybrid compound that binds the target protein to the E3 binding enzyme at the same time and achieves ubibinization of the target protein through the binding of the target protein to the E3 binding enzyme. Some researchers have pointed out that in general, E3 ubibin connective enzymes require a special identification signal to recruit to achieve ubibinization of their target proteins. The advantage of PROTAC technology is that it omits a process that makes E3 ubibinization possible for any one protein.
There is hot, from the theoretical point of view, PROTAC only provides binding activity, is the event-driven "event-driven", different from the traditional possession-driven "occupancy-drive", without directly inhibiting the functional activity of the target protein, and can be reused, so to a certain extent can overcome MDM2-p53 inhibitors due to the dose of too large and toxic and other problems. Therefore, the use of PROTAC (protein degradation target chilayer) to degrade MDM2-p53 protein-protein interactions has also become a new hot direction for drug development.
, for example, the University of Michigan recently developed a new MDM2 "degrader". Based on MDM2-p53 inhibitor MI-1061, a new type of PROTAC (MD-224) was developed.
subsequent in vitro and in vivo studies have shown that PROTAC (MD-224) is significantly more effective than the original drug (MI-1061) and has great potential for drug application without showing any toxic side effects at an effective dose (25 mg/kg (Q2D).conclusion
It is clear that the new PROTAC technology has brought new opportunities for the development of MDM2-p53 inhibitors, compared to traditional inhibitors, PROTAC from the dose, safety and other aspects have great advantages. As cancer drug developers, we may see more than just the application of such a strategy to MDM2-p53 inhibitors, a technique that could be used in the development of many other types of anti-tumor drugs. (Bio Valley)