Advances in drug research targeting BRD4
December 27, 2017 Source: Yaodu Data
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BRD4 is a full name of bromodomain-containing protein 4, a bromodomain protein 4, belonging to the BET family. The bromodomain and extra-terminal domain contain four proteins, namely BRD2, BRD3, BRD4 and BRDT. BET has a conservative modular structure: consists of two N-terminal tandem BRD effect modules (BD1 and BD2), an additional end group (ET), several conserved regions (A, B, SEED regions) and C- End zone (CTM) (Figure 1).
Figure 1. The BET bromodomain protein contains several sets of modular structures. Two N-terminal tandem BRDs (BD1 and BD2, shown in blue) are associated with acetylation recognition; an additional protein-protein interaction region (ET, shown in orange); BRDT and BRD4 long mutant (BRD4L) Contains a C-terminal region (CTM, shown as dark blue) that interacts with the forward transcription elongation factor (P-TEFb); a conserved region (A, shown in green; B, shown in deep red) and a segment rich in serine The region of glutamate-aspartic acid (SEED, shown in pink).
Studies have shown that the expression disorder of BRD4 is associated with the formation of various cancer diseases such as blood cancer, breast cancer and colon cancer. BRD3 and BRD4 are fused in error with the Nuclear Protein in Testis (NUT), leading to the development of adenocarcinoma in the NUT. BRD4 protein can participate in the transcription process of oncogenes MYC, BCL2 and BCL6 by binding to RNA polymerase II (Pol II) and positive transcription elongation factor (P-TEFb) (Fig. 2). A 2014 study by the University of New York at the Langnesi Medical Center showed that the BRD4 protein occupies the genetic position of the super-enhancer, allowing cancer cells to remain relatively immature stem-like cells, driving cancer to some extent.
Figure 2. BET bromodomain proteins are involved in the transcription of genes such as MYC, BCL2 and BCL6, which are involved in cell proliferation and apoptosis; BET bromodomain proteins play an important role in cell cycle regulation, such as involvement in cell cycle promoter A Activation of genes such as D11 and E
By targeting BRD4, tumor cell apoptosis, ie, proliferation, can be induced to slow down, thereby achieving anti-tumor effects. Therefore, BRD4 has attracted extensive attention and development in recent years as a promising anti-tumor target. The following is a brief introduction to the progress of drug development with BRD4 as the target. From the information from the drug data, there are currently 13 drugs targeting BRD4, which have entered the clinical trial research phase (from the drug data http:// Data.pharmacodia.com/), the specific information is shown in the table below, and a brief introduction to the development of some of these drugs.
The compound Apabetalone (RVX-208) is derived from a derivative of the plant Polyphenol-resveratrol. Originally developed by Resverlogix, the compound licensed R&D rights in China and Taiwan to Shenzhen Hairuipu Pharmaceuticals in 2015. This compound showed stronger inhibitory activity against BRD4 BD2 (Kd of 135 nM for BRD4BD2 and 1142 nM for BRD4 BD1). This selectivity may be due to the fact that the benzene ring of the compound forms a π−π stack with the His433 of BD2, while the corresponding amino acid in BD1 is cysteine. Apabetalone (RVX-208) is effective in reducing blood lipids in patients with hyperlipidemia. The study for the treatment of pre-diabetes is in clinical phase II for the treatment of atherosclerosis and acute coronary syndrome (ACS).
Compound CPI-0610 is an isoxazole structure BRD4 inhibitor developed by Constellation, which has an IC50 of 120 nM for BRD4. This compound has a tumor inhibition rate of 41% against acute leukemia tumors when administered orally at 30 mg/kg per day. It has also shown good efficacy in patients with lymphoma, and is currently undergoing clinical phase I trials.
Compound I-BET762 is a benzodiazepine BRD inhibitor developed by GSK Corporation. It has good permeability (167 nm/s), high solubility (>3 mg/mL), and good tissue distribution (6.5 L/). Kg) and oral bioavailability (44-61% in rats, dogs, and primates) have shown good efficacy in various tumor models and inflammatory models and are currently in clinical phase I/II.
The compound Mivebresib (ABBV-075) is a pyridone-based BRD4 targeted inhibitor developed by AbbVie which exhibits good DMPK properties with good exposure and a half-life of 25 hours. The compounds show good biological activity in various tumor models and are currently in the clinical phase I phase of treatment for solid tumors and hematological cancers.
In summary, the research on drugs targeting BRD4 has been widely concerned, and some compounds have been in clinical trials. However, the types of inhibitors reported in the literature and patents are still relatively limited, and the drug-forming properties of small molecules need to be improved. Therefore, further research on BRD4 protein for new anti-tumor drugs has great room for expansion.
references:
(1) Mass-spectrometry-based draft of the human proteome. Nature 2014, 509, 582-587.
(2) Mechanistic analysis of the role of bromodomain-containing protein 4 (BRD4) in BRD4-NUT oncoprotein-induced transcriptional activation. J Biol Chem 2015, 290, 2744-2758.
(3) The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 2005, 19, 523-534.
(4) Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J 2012, 31, 3809-3820.
(5) RVX-208: a small molecule that increases apolipoproteinA-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 2010, 55, 2580-2589.
(6) A novel BET bromodomain inhibitor, RVX-208, showsreduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis 2014, 236, 91-100.
(7) RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. PNAS 2013, 110, 19754-19759.
(8) Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials. J Med Chem 2016, 59, 1330-1339.
(9) The making of I-BET762, a BET bromodomain inhibitor nowin clinical development. J Med Chem 2013, 56, 7498-7500.
(10) Yaodu Data Pro2.0 (http://data.pharmacodia.com/)
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