A domain is a region (module) having a specific structure and independent function in a biological macromolecule (mainly referred to as a protein).
Bromodomains (BD) are protein domains consisting of approximately 110 amino acid residues that recognize the acetylation of the tail of histones (the major protein component of chromatin, which together form a nucleosome structure with DNA). A residue that specifically binds to it. Acetylation of histones is a prerequisite for activating gene transcription and expression. Therefore, bromodomain proteins can control transcription and play an important role in epigenetics in the role of "Reader".
The bromodomain (BD) was named for its initial discovery in the Drosophila Brahma/brm gene and was not associated with the chemical element bromine. BD is a conserved protein sequence found in all eukaryotes. The human proteome contains a total of 61 BDs distributed among 46 proteins.
BD has good small molecule binding potential and experimental operability, and there is a large amount of evidence that dysfunction of BD protein is associated with various cancers, inflammatory diseases, viral infections and the like. At home and abroad, great success has been achieved in the discovery of small molecule BD inhibitors (BDi) with good drug properties (such as cell permeability). These small molecules block the binding of BD to cellular targets. Early BDi discovery was based on cell-based phenotypic screening, and currently more focused on fragment-based ligand discovery methods.
From a chemical and structural point of view, BDi drugs are attractive. At least 24 BDi have entered clinical trials for indications such as cancer, type 2 diabetes, cardiovascular disease and coronary artery disease, and this field has also emerged in the past decade. Most drugs only reach the early clinical stage, domestically. There are no such drugs on the market. For domestic innovative drug development companies, the bromine domain (BD) is an ideal target for innovative drug deployment.
BET is a very important class in BD, which is referred to as the bromodomain and the terminal extradomain. It is characterized by two conserved bromodomains (BDI and BDII) at the N-terminus and an ET (extraterminal) domain at the C-terminus. The family consists of four members, BRD2, BRD3, BRD4 and BRDT. In the early stages of cell research, BET inhibitors (BETi) have shown profound biological effects.
Given the preclinical activity of BETi and its links to key cancer transcriptional regulatory networks, a number of clinical trials have been conducted, targeting cancer indications. Giants including MSD, GSK, BMS, Roche, Bayer, AZ, etc. have begun to layout. See the table below.
The BETi in the clinical stage is a mimetic of acetylated lysine, and the heterocyclic skeleton in the structure occupies the pocket of BD. Many drug candidates contain azaindole/diazepine-like structures, including MK-8628 or OTX-015 (Merck and Oncoethix), CPI-0610 (ConstellationPharma), GSK525762 (GSK), and RO6870810 (Roche), while other compounds It is a more diverse structure. A new generation of BETi selectively targets BDI or BDII and is better tolerated.
The BDII bromodomain is highly conserved among the BET family members (>70% homology). A representative selective BETi is Abbott's ABBV-744, which is a second-generation BDII inhibitor with selectivity. Compared to the first generation BETi with improved bioavailability and tolerance, it is currently in Phase I trials of solid tumors and blood cancer. Preclinical studies have shown that ABBV-744 is effective at doses well below MTD, while non-selective BETi is effective at doses close to MTD.
BPI-23314 is a potent, highly selective small molecule BETi approved for clinical trials of malignant hematological tumors (AML, NHL and MM) earlier this year.
In phase I clinical (n=64) with CPI-0610 for relapsed or refractory lymphoma, the most common TEAEs were thrombocytopenia, fatigue, nausea, loss of appetite, and anemia. However, thrombocytopenia is reversible and has no cumulative effect. Five patients achieved OR, including 2 CR and 3 PR, and 5 patients had prolonged SD (>6 months), indicating that CPI-0610 is well tolerated and clinically active in advanced lymphoma.
BETi can block macrophage production of cytokines and reverse septic shock in mice. Further studies have reported extensive anti-inflammatory activity of various BETis. In addition to inflammatory diseases, BETi also reverses cardiac damage in heart failure mice by regulating cardiomyocyte transcriptional processes, and thus has potential for widespread use in inflammatory diseases.
Apabetalone (also known as RVX-208/RVX-000222) was developed by Resverlogix, Canada. In 2017, Hai Purui increased its investment in Resverlogix by approximately RMB 460 million and obtained exclusive market license rights for its patented product RVX-208 in China, Hong Kong, Macau and Taiwan.
The drug is currently undergoing Phase III clinical trials in patients with type 2 diabetes who are at high risk for cardiovascular disease, with the primary endpoint being a reduction in major cardiovascular adverse events.
In Phase II, RVX-208 reduces the abundance of various vascular inflammatory mediators in the plasma of patients with cardiovascular disease, including adhesion molecules, cytokines, and metalloproteinases, thus potentially reducing cardiovascular disease risk.
Preclinical and early clinical studies have shown that RVX-208 has a beneficial effect on apolipoprotein and HDL levels, glucose metabolism, cholesterol transport, vascular inflammation, coagulation and complement cascades. Although other BETi also have some of the same pharmacological effects, the diversity of RVX-208 action has not been observed in other BETi. In contrast, RVX-208 has the least impact on other BETi-targeted key cancer transcription networks.
Given the close link with disease, the most promising non-BETBD targets are the transcriptional coactivators CREBBP and EP300. The association of CREBBP and EP300 with cancer and other diseases has been demonstrated by mouse genetics and human tumor sequencing experiments.
Selective inhibition of the bromodomains of CREBBP and EP300 produces limited transcription and anti-proliferative effects. This lower activity of CREBBP and EP300BDi relative to BETi may actually be beneficial for clinical development, contributing to increased tolerance and definitive patient identification. The group is conducive to the efficacy in early clinical practice. CellCentric has initiated Phase I/IIa clinical trials to study the role of CCS1477 in metastatic prostate cancer and other solid tumors, making CREBBPEP300 the second clinically accessible BD target. The selectivity of CCS1477 for CREBBP and EP300 is 170 times that of BRD4.
It has been reported in the literature that some kinase inhibitors also have a BD domain.
LY294002 is a selective and reversible PI3K inhibitor (IC50 500nM~ 973nM), while inhibiting the BRD2, BRD3 and BRD4 domains of BET protein (IC50 1-2μM).
The prodrug SF1126 of LY294002 was used in Phase I clinical studies, and pharmacological experiments showed that it reduced phospho-S6 kinase and reduced tumors. Clinical trials are exploring the use of a single dose of SF1126 in a variety of solid tumors. In addition, the multi-kinase inhibitor sorafenib is effective in combination with SF1126 in a preclinical animal model of hepatocellular carcinoma, supporting the planned phase II clinical trial.
