Talking about the BRD4 inhibitors under clinical research

Text|Star Fox

As early as 2010, nature reported the first-in-class small molecule BRD4 inhibitor, and since then, the research boom of BRD4 as a hot target has been unveiled
.

01 BRDS research background

Bromodomain (BRDS) is a conserved protein domain that can specifically recognize acetylated lysine residues in proteins.
According to the similarity of structure and sequence, 61 human bromodomains are divided into 8 families, of which BET family proteins The most representative and include BRD2, BRD3, BRD4, and BRDT, the BET family bromodomain protein BRD4 contains acetylated lysine residues that can bind to histones and other proteins, and plays a role in regulating genes and controlling cell growth.
Playing an important role, BRD4 protein is related to large protein complexes that regulate gene transcription, including mediators, PAFc, and super-elongation complexes
.

Many human diseases are closely related to BRD4 protein, such as tumors, autoimmune or inflammatory diseases, and viral infections
.

BRD4 protein contains two subtypes BD1 and BD2.
In view of their high sequence similarity, it is challenging to obtain selective inhibition in the BET family.
Therefore, pan-BET inhibitors (such as (+)-JQ1 and iBET-151) Etc.
) It is widely used in the functional study of BET protein by inhibiting multiple bromine domains at the same time
.

02 BRDS target prospects

Next, for the BRD4 inhibitors under clinical research, talk about the prospects of this target, which only represents my personal opinion
.

Figure 1 Some BRD4 inhibitors under clinical research

SYHA 1801 is a BRD4 inhibitor developed by CSPC.
It is indicated for solid tumors.
Based on public information, no public structure has been found.
The author found that WuXi DDSU and CSPC jointly applied for one in September 2017.
Compound patent (WO2019056950A1).
According to this patent and subsequent patent layouts, SYHA 1801 should be modified based on TEN-010.
In view of the fact that Roche developed TEN-010 in multiple indications (acute myeloid leukemia; breast cancer; diffuse large B-cell lymphoma; multiple myeloma; ovarian cancer; solid tumors) are almost wiped out.
The author holds a negative attitude towards CSPC’s SYHA 1801
.

Apabetalone (RVX-208) is a BRD4 inhibitor of quinazolinones developed by Resverlogix.
Its selectivity for BD2 is 170 times higher than that of BD1.
The indications currently in clinical phase III include: Acute Coronary Syndrome Atherosclerosis; low high-density lipoprotein cholesterol; it has not yet been developed for tumor-oriented indications.
At present, this type of BD2 selective BRD4 inhibitor has a good prospect
.

INCB 057643 was developed by Incyte.
Although the indications in the direction of cancer have ended, Incyte has not given up.
In 2021, a phase II clinical trial was launched for myelofibrosis
.

PLX-2853 was jointly developed by Plexxikon and Daiichi Sankyo.
The current clinical indications include gynecological cancer and hematological malignancies; the structure has not yet been disclosed.
Plexxikon has another molecule that has entered the clinic, namely PLX-51107, but its It has failed in multiple indications and is currently developing a preclinical treatment for graft-versus-host disease; the author inquired about the BRD4 inhibitor patent applied by Plexxikon, and its skeleton is similar.
PLX-2853 should be different from PLX-51107.
Not very big, and its follow-up prospects are not optimistic at present
.

CC 90010 is a small molecule inhibitor of isoquinolinones developed by Xinji Company, which was later acquired by BMS and can be found in the clinical pipeline of BMS
.

AbbVie’s ABBV-075 and Constellation’s CPI-0610 have failed clinically in the direction of cancer, and are currently developing indications for myelofibrosis; ABBV-075 and INCB 057643 both have pyrrolopyridone cores.
Skeletonoids seem not to go far in the direction of cancer
.

AstraZeneca’s AZD 5153 has also failed clinically in the direction of lymphoma and solid tumors, and is currently undergoing phase II clinical combination therapy to treat myelofibrosis
.

Boehringer Ingelheim's BI-894999 is a pyridoimidazole followed by a pyridazinone fragment.
The current clinical indication in the first phase is diffuse large B-cell lymphoma; solid tumors
.

BMS-986158 is a second-generation BET inhibitor developed by BMS.
Subsequently, BMS developed BMS986225 as a backup.
Compared with 986158, it mainly introduces F to improve membrane permeability, uses deuterium to improve metabolic stability, and introduces The pyridine fragment increases solubility without adversely affecting PK
.

GS 5829 developed by Gilead is a small molecule of benzimidazole.
The three tumor indications that have been queried on Clinicaltrials have been terminated
.

Figure 3 PROTACs for drug-resistant BET

Currently, some pan-bet inhibitors are in clinical trials for the treatment of different cancers
.

03 Existing problems and breakthrough directions

The clinical trial results published so far raise several key issues that need to be considered
.

First, some inhibitors have shown toxicity in clinical trials, including dose limiting toxicity (DLT)
.

The most common adverse reactions are thrombocytopenia, diarrhea, fatigue, vomiting, anemia and hyperbilirubinemia
.

In addition, complications and immune deficiencies are potential adverse reactions to the use of pan-bet inhibitors
.
The Phase I trial of BAY1238097 was terminated early due to severe toxicity, and the production of INCB057643 was also discontinued for safety reasons
.

Second, the anti-tumor activity of some inhibitors is much lower than that observed in preclinical trials
.

In the CPI-0610 dose study of 44 patients with relapsed or refractory lymphoma, only 2 cases had a complete remission and 1 case had a partial remission
.
In addition, OTX-015 and IBET151 were forced to terminate due to their limited efficacy on solid tumors
.
Pan-bet inhibitors show a significant survival advantage in tumor models, and this is often cancelled in drug-resistant cell transplantation
.

The main reason for the lack of clinical efficacy may be the failure to determine the correct group of patients most likely to benefit from pan-bet inhibitor treatment, resulting in ineffective administration before the occurrence of DLT
.
In addition, the modest results may be partly attributable to the development of resistance, which reduces the clinical response to pan-bet inhibitors
.

Therefore, the following clinical breakthroughs are mainly centered on three aspects-

First, look for highly selective inhibitors against BD1 or BD2 or BRD4 to reduce off-target and reduce the occurrence of side effects;

Second, look for dual-target inhibitors to solve the problem of drug resistance from related pathways such as AMPK;

Thirdly, PROTAC is aimed at BRD4 to solve the problem of drug resistance.
Currently, no degradation agent for BRD4 has entered the clinic
.

references:

1.
Pan Tang et al.
Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development.
J.
Med.
Chem.
2021, 64, 2419−2435.

2.
Yu Rao et al.
PROTACs as Potential Therapeutic Agents for Cancer Drug Resistance.
Biochemistry 2020, 59, 240−249.

3.
Andrew P.
Degnan et al.
Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128108.

4.
Fan Lei, Wang Fei, Wu Xiaoquan, etc.
; CN10776508B.