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GSK and AbbVie are both under development, and Betta Pharmaceuticals and Jiaxi Pharmaceuticals are accelerating. What is the development potential of BET inhibitors?

 Last Update: 2021-09-19
 Source: Internet
 Author: User

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Recently, the research and development of BET inhibitor drugs has successively ushered in new progress.
Many Chinese companies including Betta Pharmaceuticals, Gacus Pharmaceuticals, and Wenda Pharmaceuticals have made new research progress in BET inhibitors
.
Scientists have been exploring the target of BET for more than 20 years.

Although no BET inhibitor has been approved for marketing globally, relevant clinical research is advancing rapidly

Related to a variety of diseases, over 40 cancer-related clinical studies

Speaking of BET, we have to mention the bromodomain (BD) first

▲ BET protein structure (picture source: reference [2])

▲ BET protein structure (picture source: reference [2]) BET protein structure (picture source: reference [2])

The BET protein family contains four isoforms: BRD2, BRD3, BRD4 and BRDT
.
Each family member contains two highly conserved bromo domains (BD1, BD2) and an ultra-terminal domain (ET)

Bromodomain super terminal domain

BET family proteins can bind to acetylated chromatin through their bromodomains, thereby regulating gene expression at the epigenetic level
.
With the deepening of research, researchers have discovered that the BET protein family plays an important role in the occurrence and development of many tumors, such as acute leukemia and lymphoma, by regulating the biological processes of cell cycle, proliferation and differentiation, and apoptosis and autophagy.

and breast cancer

Regulate gene expression at the epigenetic level

Therefore, the BET protein family is considered as a new therapeutic drug target in the field of epigenetics
.
Currently, a series of BET inhibitors are in clinical trials to test their efficacy in treating a variety of cancers including leukemia, lymphoma, brain tumor and myeloma

The BET protein family is considered to be a new therapeutic drug target in the field of epigenetics

▲ Relevant clinical research carried out by BET inhibitors in the field of cancer ( picture source: reference [2])

▲ Relevant clinical research carried out by BET inhibitors in the field of cancer ( picture source: Reference [2]) Relevant clinical research carried out by BET inhibitors in the field of cancer ( picture source: Reference [2]) Picture source: Picture source:

New BET inhibitors are under development

Since the four subtypes of the BET protein family have a high degree of homology, it is extremely challenging to find a highly selective BET inhibitor

Pan BET Inhibitor

The aforementioned review article summarized and pointed out that BET inhibitors face many challenges in clinical development : On the one hand, some BET inhibitors have shown toxicity in clinical trials, including dose-limiting toxicity; on the other hand, some BET inhibitors have anti-tumor activity It is lower than that observed in preclinical studies, which may be that patients who have not been selected to benefit from BET inhibitor treatment; in addition, the emergence of drug resistance also weakens the efficacy of BET inhibitors
.

BET inhibitors face many challenges in clinical development

In order to solve these problems, the development of BET inhibitors with high subtype selectivity is a new direction at present
.
The aforementioned review article also pointed out that the current selective BET inhibitors are the main development direction, including BD1 selective inhibitors, BD2 selective inhibitors and BRD4 selective inhibitors

In order to solve these problems, the development of highly subtype selective BET inhibitors is a new direction at present

For example, compound JQ1, as one of the earlier reported BET small molecule inhibitors, has a wide range of diseases.
However, due to its short half-life in cells, large dosages, and greater toxicity during treatment, researchers have begun Optimized and modified on the basis of JQ1, and further obtained a selective BET inhibitor with long-lasting efficacy and good inhibitory activity
.
For example, CPI-0610 (pelabresib), which is being developed by Constellation Pharmaceuticals, is based on JQ1, replacing the metabolically unstable thiophene ring with a modified compound

.
It is reported that its inhibitory activity on BD1 is more than 6 times that of BD2
.
In 2019, CPI-0610 showed good activity in patients with myelofibrosis in a phase 2 clinical trial
.
At present, the research project has launched a global phase 3 clinical trial to test the efficacy of its combination with JAK inhibitors in the treatment of myelofibrosis
.

At present, several BD1 selective inhibitors have also been reported
.
For example, GSK778 of GlaxoSmithKline (GSK) has an affinity for BD1 130 times higher than that of BD2, and GSK789 obtained by further modification has a selectivity for BD1 that is more than 1000 times higher than that of BD2
.

The affinity to BD1 is 130 times higher than that of BD2, and the GSK789 obtained by further modification.
The selectivity to BD1 is more than 1000 times that of BD2

Based on AbbVie's pan-BET inhibitor ABBV-075, ABBV-744 is a highly effective BD2 selective inhibitor with a selectivity of more than 300 times higher than BD1
.
Preclinical studies have shown that the modified ABBV-744 can improve tolerance to a certain extent
.
Currently, the candidate drug is in phase 1 clinical trials and is being developed for the treatment of solid tumors and hematological malignancies
.

ABBV-744 is a highly effective BD2 selective inhibitor

At the same time, inhibitors specifically targeting BRD4 are also emerging
.
The research point of view points out that it is very important to improve the selectivity of BRD4 inhibitors in specific biological processes and disease processes, especially for the treatment of cancer and inflammation
.

In addition, some dual-target inhibitors for BET are also under study
.
There are also some new treatment technologies and treatment methods for the BET protein family being explored, and the more representative one is the protein degradation therapy PROTACs
.
Among the currently publicly reported PROTAC compounds, many drug candidates target BRD4.
However, the exploration in this area is still in the early stage, and the therapeutic potential needs to be further clinically verified
.

Research progress of many BET inhibitors under research in China

In the field of BET inhibitors, many companies in China are currently developing related products
.
Betta Pharmaceuticals recently announced that its third clinical trial application for BET inhibitor BPI-23314 tablets has been approved by the National Medical Products Administration (NMPA), and the proposed development indication is malignant hematological tumors (including but not limited to MF, etc.
) Myeloproliferative tumors and myelodysplastic syndromes)
.
Previously, the drug has been approved to carry out single-agent clinical trials for malignant hematological tumors (acute myeloid leukemia, non-Hodgkin's lymphoma and multiple myeloma) and for advanced malignant solid tumors
.

Preclinical data shows that BPI-23314 can not only inhibit the expression of various cancer genes related to BET and degrade the target protein BRD4 , but also effectively inhibit the activation of inflammation-related signal pathways and the expression of inflammatory factors
.
The early clinical results for hematoma showed its good safety and PK properties, and it is expected to provide a new molecule targeted to degrade proteins
.

BPI-23314 can not only inhibit the expression of multiple cancer genes related to BET and degrade the target protein BRD4

Another NHWD-870 HCl tablet from Wenda Pharmaceuticals, which is also a selective inhibitor targeting BRD4, has obtained two clinical implied licenses in China and is intended to be developed for the treatment of advanced relapsed non-Hodgkin's lymphoma , Skin/mucosal melanoma, non-small cell lung cancer and small cell lung cancer
.
According to the research results published in Nature Communications in April 2020, NHWD-870 HCl tablets showed strong anti-tumor activity in different mouse tumor models
.
Recently, Wenda Pharmaceutical announced that it has obtained 100 million yuan in Series A financing, and will continue to promote the development of anti-tumor clinical trials of this research project
.

There are also products under development that target BET in the pipeline of Jacos
.
Its BET inhibitor JAB-8263 is undergoing phase 1 clinical trials for solid tumors simultaneously in China and the United States
.
Preclinical studies have shown that JAB-8263 can exert anti-tumor effects on a variety of solid tumors and hematomas
.

Its BET inhibitor JAB-8263 is currently undergoing phase 1 clinical trials for solid tumors in China and the U.
S.

In addition to cancer, BET inhibitors are also expected to play a role in other diseases
.
For example, the selective BET inhibitor RVX-208 for BD2 developed by Resverlogix has entered phase 3 clinical trials
.
Earlier, the FDA granted RVX-208 breakthrough therapy designation for secondary prevention of major adverse cardiovascular events in type 2 diabetes patients who have recently experienced acute coronary syndromes
.
It is worth mentioning that Haipurui has the exclusive right to develop and commercialize the innovative drug in Greater China
.

In addition to cancer, BET inhibitors are also expected to play a role in other diseases

In short, scientists' exploration in this field is still in progress
.
For example, a recent study published in a sub-Journal of Nature showed that compared with monotherapy, BET inhibitors combined with MDM2 inhibitors are more effective in the treatment of acute myeloid leukemia (AML) and can significantly accelerate cancer cell death
.

As the research on BET continues to deepen and improve, it is believed that more highly active and highly selective BET inhibitors will be designed and developed.
We look forward to new breakthroughs in clinical research on this target this morning and bring new breakthroughs to patients as soon as possible.
Treatment options
.

Reference materials:

[1] Cao Ran, Li Yu et al.
(2020).
Research progress of BET bromine domain inhibitors.
"Chinese Journal of Medicinal Chemistry" DOI: 10.
14142 /j.
cnki.
cn21-1313 /r.
2020.
06.
005

[2]Pan Tang, Jifa Zhang et al.
(2021).
Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.
Journal of Medicinal Chemistry, DOI: 10.
1021/acs.
jmedchem.
0c01487

[3] Wang Zeyu, Chen Zhuo, Li Ganbin.
(2017).
Research progress of bromodomain protein 4 and its inhibitors.
"Chinese Pharmaceutical Journal" DOI: 10.
11669 /cpj.
2017.
15.
001

[4] Chen Jinjing, Zhao Xiaoli, etc.
(2017).
Family proteins containing bromine domains and additional terminal domains-a new therapeutic target in the field of epigenetics
.
"Acta Pharmaceutical Sciences" DOI:: 10.
16438/j.
05l3-4870.
2017-0143

[5]MorphoSys to Acquire Constellation Pharmaceuticals.
Retrieved June 2.
2021.
from https://morphosys-constellation-royaltypharma.
com/wp-content/uploads/2021/06/MorphoSys-Constellation-Announcement-Investor-Presentation.
pdf

[5] Jacos-B: Interim results announcement for the six months ended June 30, 2021.
Retrieved Aug 31.
2021.
from http:// hke&orgId=9900047696&stockCode=01167&announcementId=1210948916&announcementTime=2021-08-31%2021:46

[6] Haipurui: 2021 semi-annual report.
Retrieved Aug 27.
2021.
from http:// Haipurui: 2021 semi-annual report.
Retrieved Aug 27.
2021.
from http://

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