Talking about the BRD4 inhibitors under clinical research, some are advancing, some are struggling

 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
.

Currently, some pan-bet inhibitors are in clinical trials for the treatment of different cancers
.
However, the clinical progress of most pan-bet inhibitors is still in the early stages, mainly focusing on cancer treatment
.

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
.
A common DLT is thrombocytopenia, but platelet function is not impaired, and the decline in platelet count is reversible and can be restored within 1 week after stopping the drug
.

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.