executive Summary
Protein-targeted degradation is the most cutting-edge mechanism of small-molecule drug-making. There are more than 10 technical paths to carry out related research. The most well-known ones are PROTAC and molecular glue. Targeted protein degradation utilizes two naturally occurring protein degradation systems in the human body: the ubiquitin-proteasome system and the lysosome system to achieve efficient and precise degradation of pathogenic proteins. Based on these two major protein degradation systems, various technical paths have been extended.
PROTAC has three significant advantages. First, it is expected to overcome drug resistance, second, it is expected to turn “unpreparable” into “drug”, and third, it is expected to be “best-in-class”. PROTAC also has many challenges. The first is that the pharmacokinetics and efficacy are unknown, and there is a lack of data on higher species. Poor membrane permeability, beyond the five principles of drug-like. There is also a lack of efficient triplet screening methods, resulting in a huge amount of PROTAC synthesis work in practice. The understanding of degradation is still incomplete, and it is difficult to form ternary complexes due to the HOOK effect after drug delivery.
The protein degradation technology represented by PROTAC has completed the proof of concept and entered the initial transformation stage. Proteolysis began in 1999, and interest in PROTACs began to grow in 2015 when the labs of Bradner, Ciulli and Crews developed improved molecules. And started the first clinical trial in 2019.
In terms of policy, my country issued the “14th Five-Year Plan for the Development of the Pharmaceutical Industry”, focusing on proposing that PROTAC is the key development direction of innovative technologies. On January 30, 2022, nine departments including the Ministry of Industry and Information Technology jointly released the “14th Five-Year Plan for the Development of Pharmaceutical Industry”, which listed cutting-edge core technologies and drugs including PROTAC’s targeted protein degradation technology as key development object. Many companies at home and abroad have deployed protein degradation through independent research or commercial cooperation. About 20 domestic companies participated in the layout. Nearly half of the existing protein degradation companies were established in 2017-19. Representative companies include Haichuang Pharmaceutical, etc., and overseas representative companies include Arvinas, C4, Kymera, etc.
The popularity of the protein degradation track will start in 2021. The disclosed amount of cooperative projects exceeds 6 billion US dollars, with an average of one per month. In the past year, MNC has reached 14 commercial cooperation projects in the protein degradation track, which is the total number of projects achieved before 2021.
At present, 31 protein degraders have entered clinical trials, and the most advanced pipeline is in clinical phase II. The main application of protein degradation technology is in the field of anti-tumor. The existing pipeline targets are relatively concentrated, and most of them are already verified targets.
The clinical trial results of the first PROTAC degraders show that the PROTAC molecule has ideal safety and clinical efficacy, and is expected to be the best in class. The clinical results answer the four most critical questions: first, PROTAC molecules can be used as drugs; second, they are safe; third, they can degrade target proteins; fourth, they have therapeutic effects on diseases.
On the technical side, how will targeted protein degradation develop in the next 20 years? The first is to define and interpret the most suitable target types for clinical degradation; the second is to expand the map of E3 ligases to achieve precise treatment; the third is to extend indications beyond tumors; the fourth is to clinically validate molecular glue and protein degradation technologies other than PROTAC path.
On the industrial side, where will targeted protein degradation go in the future? The research and development of small molecule innovative drugs is difficult, but the supporting industry chain is mature and the competition pattern is good. With the continuous disclosure of the existing encouraging clinical results, the next 20 years must be the 20 years of inflection point development of the protein degradation track.
On the capital side, since 2015, the global capital fever has surpassed technological progress. In 2020, three overseas companies (C4, Kymera, Nurix) received IPOs. At that time, none of the three companies had clinical assets. The development of the field of protein degradation in the past three to five years will largely depend on the clinical results of the first drugs, and the 22/23 clinical trials are crucial.
To view the full report click here
Note: The articles on this site have not been posted and shared by netizens or institutions unless they are marked as original. If there is any need for publicity or infringement, please contact [email protected].
This article is reproduced from: https://www.dx2025.com/archives/170717.html
This site is for inclusion only, and the copyright belongs to the original author.