The development of PROTAC drugs is being developed at the time, and Baekje and Haisco continue to make efforts

On October 26, the clinical application of BeiGene BTK PROTAC new drug BGB-16673 film-coated tablets was accepted by NMPA

PROTAC (Proteolysis-targeting chimera) stands for protein degradation targeted chimera, which uses the ubiquitin-proteasome system to induce targeted protein degradation

The concept of PROTAC

PROTAC technology is an emerging direction for drug research and development.

Figure: PROTAC mechanism of action

Compared with small molecule drugs, the biggest feature of PROTAC drugs is that they only provide binding activity without directly inhibiting the target protein

First, target non-druggable proteins to overcome the problem of drug resistance

Second, the safety of the drug is high

Third, it can target structural proteins

Although PROTAC has shown significant advantages, there are still some problems that need to be solved urgently

First, the molecular weight is larger and the membrane permeability is poor

Second, PROTAC development is more difficult

Picture: PROTAC drug is poorly prepared

Data source: Fendi Technology

Table: Comparison of traditional small molecule drugs, monoclonal antibodies, PROTAC, and RNA drugs

PROTAC research and development progress in my country

Currently, no PROTAC drug has been approved for marketing in the world

Table: List of domestic PROTAC drugs under research (incomplete statistics)

(1) Pioneer Pharmaceutical: The GT20029 of Pioneer Pharmaceutical is the first PROTAC approved for clinical use in China and the world's first AR-PROTAC for external use

It is worth mentioning that, in view of the obstacles of PROTAC's large molecular weight and poor oral bioavailability, Kaifeng Pharmaceutical did not insist on oral administration, but bypassed the bottleneck of poor oral availability and developed topical, topical The AR degradant administered to the skin effectively reduces drug exposure while improving the local efficacy of the drug

(2) Haisco: HSK29116 is a class 1 innovative chemical drug developed by Haisco.

(3) BeiGene: BeiGene’s BGB-16673 is a BTK-targeted protein degradation agent, and is the second BTK-PROTAC that has been declared for clinical use in China

Picture: BeiGene CDAC Platform

Data source: BeiGene

(4) Haichuang Pharmaceutical: Haichuang Pharmaceutical has three PROTAC drugs, namely AR-PROTAC HP518, AR-sv-PROTAC HC-X029 and SHP2-PROTAC HC-X035

HP518 is an oral PROTAC drug that degrades AR to treat prostate cancer
.
Its mechanism of action is to simultaneously recognize and connect the target AR and E3 ligase through the target recognition part of the PROTAC molecule and the E3 ligase recognition part, respectively, to bring the two closer together, and to promote the transfer of ubiquitin protein to the target protein.
The protein-proteinized labeling promotes the degradation of the target protein through the proteasome
.

In preclinical studies, HP518 showed good oral bioavailability, and showed good anti-tumor activity in prostate cancer animal model studies
.
According to published data, the in vitro biological activity and efficacy of HP518 are comparable to Arvinas' ARV-110, but there is no problem of interaction with statins published by ARV-110.
HP518 is expected to have better safety and wider coverage.
The patient population and scope of application
.

Figure: ARV-110 and HP518 test data comparison

Data source: Haichuang Pharmaceutical

SHP2 is an upstream positive regulator in the RAS-ERK pathway.
Its activating mutations can promote tumor formation and growth.
Inhibition of SHP2 can block the cancer-promoting function of the RAS-RAF-ERK pathway, leading to cancer cell growth inhibition and induction of apoptosis
.
HC-X035 is the world's first PROTAC drug that targets the degradation of SHP2 independently developed by Haichuang Pharmaceutical.
It can specifically bind to SHP2 and induce its degradation, inhibit the formation and growth of tumor cells, so as to achieve the purpose of treating tumors
.

summary

As a new small molecule drug technology, PROTAC can act on pathogenic proteins that cannot be inhibited by traditional targeted drugs, changing the target from "drugless" to "drugged"
.
At present, more than ten domestic companies have been deeply engaged in PROTAC drugs, including Kaifeng Pharmaceutical, Haisco, BeiGene, Haichuang Pharmaceutical, Lingke Pharmaceutical, Fendi Technology, etc.
, among which Kaixin Pharmaceutical, Haisco, Baiji China's economic PROTAC drugs already in clinical stage ⅰ
.
Considering that the global PROTAC leader Arvinas' ARV-471 is still in clinical phase I/II, PROTAC drugs may become the key for domestic innovative drug companies to achieve curve overtaking.
I sincerely hope that relevant companies will make rapid progress in the research and development of PROTAC drugs and settle down as soon as possible.
Fruitful
.