Personalized Medicine in Lung Cancer
II-Jin Kim in Cancer Genetics and Genomics for Personalized Medicine, 2017
Finally, transcription can be disrupted via targeting of associated transcriptional complex components. In some cases, agents bind covalently to TFIIH and inhibit its ATPase activity. This action disrupts the opening of double-stranded DNA for RNPII transcription and repair as well as RNPI transcription. Therefore, cytotoxicity of these drugs is associated with transcriptional inhibition of anti-apoptotic factors and induction of apoptotic factors.55, 56 BRD3 and BRD4 are important emerging targets for treatment of various cancers. Displacement of BET bromodomains from chromatin prevents BRD3 and BRD4 reader activity. Inhibition of these factors has a generalized effect on RNPII transcription which causes downregulation of BCL-2, MYC and CDK6, thereby inducing cell cycle arrest and apoptosis.57, 58–59 Usually, transcription inhibition induces apoptosis by four possible mechanisms: altering the balance of apoptotic and anti-apoptotic factors to favor apoptosis, activating p53 and promoting its translocation to mitochondria, inhibiting DNA replication, and promoting accumulation of aberrant proteins in the nucleus. Moreover, oncogenes that are frequently overexpressed in cancer cells can be suppressed via transcription inhibition without affecting other genes (Fig. 2.8).
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
The bromodomain and extraterminal bromodomain (BET) protein inhibitor, JQ1, which inhibits BRD4 by competitive inhibition of the acetyl-lysine recognition motif, has been shown to reduce cell viability due to arrest at G1 phase followed by an increase in tumor cell apoptosis in an MYC-amplified MB model. JQ1 suppressed MYC expression and inhibited MYC-associated targets [85-87]. Similarly, other BRD4 inhibitors are under current investigation [88]. A cyclin-dependent kinase inhibitor, alsterpaullone (ALP), was shown recently to reduce cell proliferation in vitro and improve mortality in an in vivo mouse model of Group 3 MB via the downregulation of MYC expression [89]. Additionally, the folate synthesis inhibitor, pemetrexed, and the nucleoside analog, gemcitabine, demonstrated a synergistic effect in reducing neurosphere proliferation in vitro, inhibiting tumor cell proliferation in vivo, and increasing the survival of mice bearing MYC-overexpressing tumors [90, 91].
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Optimization of the degrader is needed for efficient and selective degradation of target proteins. Useful information is the crystal structure of the ternary complex, the target protein-SNIPER, or PROTAC-E3 ubiquitin ligase, although there is room for discussion on how these data should be used for development of SNIPERs and PROTACs. Recently, Dr. Ciulli’s group solved the crystal structure of MZ1 (a VHL-recruited PROTAC against BRD4)-bound ELOB-ELOC-VHL-BRD4BD2 (the second bromodomain of BRD4) complexes, and found that cooperative binding of VHL to BRD4BD2 contributes to effective and specific degradation of BRD4BD2 by the PROTAC (Gadd et al., 2017). Based on the crystal structure, they developed a highly selective and novel degrader of BRD4 (Gadd et al., 2017). Similarly, Dr. Fischer’s group resolved the crystal structures of dBET (CRBN-recruited PROTAC against BRD4)-bound DD1BΔB [harboring an internal deletion of the flexible BPB propeller (Petzold et al., 2016)]-CRBN-BRD4BD1 (the first bromodomain of BRD4) complexes. However, X-ray crystal structures together with biochemical, cellular, and computational characterizations showed that the effective activity and selectivity of the degraders did not correlate with the strong binding or positive cooperativity between CRBN and BRD4 (Nowak et al., 2018). They demonstrated the plasticity between CRBN and BRD4, which results in several distinct low energy binding conformations, leading to the effective activity and selectivity of the degrader-induced protein degradation. In addition, they demonstrated that in silico protein docking can facilitate the design of a BRD4-selective degrader (Nowak et al., 2018). Thus, the effect of cooperativity between the target protein and E3 ubiquitin ligase on the activity and selectivity of degradation remains unclear. It might be dependent on the combination of the E3 ubiquitin ligase and target protein, and the issue should be resolved in the future. Because crystal structure analysis could be helpful to design and develop highly selective degraders, such analysis together with in silico protein docking should be performed to optimize SNIPERs and PROTACs.
Inhibition of BRD4 Suppresses the Growth of Esophageal Squamous Cell Carcinoma
Published in Cancer Investigation, 2021
Haiyu Niu, Feixue Song, Hanwen Wei, Yuan Li, Hao Huang, Changping Wu
BRD4 is frequently imperative for the expression of Myc and other “tumor-driving” oncogenes in hematologic cancers, such as glioma, multiple myeloma, acute lymphoblastic leukemia, and acute myelogenous leukemia. BRD4 is a principal target of BET inhibitors, a category of pharmaceutical drugs presently being assessed in clinical trials (42,43). The profiles of gene expression have shown that BRD4 is expressed in an extensive range of somatic cells. In addition, ChIP-seq data illustrated that BRD4 acts as an enhancer and promoter of gene expression in both cancer and non-cancer cells (44). A previous study demonstrated that BRD4 knockdown had negligible or no impact on the expression of MMP9 and CCL2 mRNA. However, BRD4 inhibition after JQ1 treatment led to a significant decrease in the TNF-α-inducible MMP9 and CCL2 mRNA levels (45). Both BRD4 mRNA and protein expression are associated with the BRD4 copy-number in high-grade serous ovarian cancer (46).
A patent review of BRD4 inhibitors (2013-2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Tian Lu, Wenchao Lu, Cheng Luo
Therefore, we propose to first discover many new fragments through fragment screening, rational design, bioelectron decomposition and eutectic analysis, and develop more with the help of traditional drug discovery methods [133]. Second, the role of BRD4 is to target key transcriptional networks. Therefore, the transcriptional effects of BRB4 inhibition are highly dependent on the environment and can be modified by a variety of cellular and non-autonomous stimuli, in the absence of linkages to disease-related pathways. Extensive preclinical activity preclinical activities can be translated into effective clinical outcomes. Similarly, compelling joint trials should also be supported by equally compelling data that mechanically links drug targets and provides clear criteria for patient selection. Therefore, it is important to develop and improve in vivo target validation assays for BRD4 inhibitors to ensure their safety and efficacy.
Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia
Published in OncoImmunology, 2021
Aroa Baragaño Raneros, Ramon M Rodriguez, Aida Bernardo Flórez, Pilar Palomo, Enrique Colado, Alfredo Minguela, Beatriz Suarez-Alvarez, Carlos López-Larrea
The initial step in the binding of BRD4 to regulatory regions is the recognition of acetylated residues in histones, a characteristic of active promoters. After that, BRD4 recruits the P-TEFb (CDK9/cyclin T) complex that phosphorylates to the RNA polymerase II (Ser2) promoting the transcriptional elongation.21 ChIP assays with specific mAb showed enrichment of total acetylation levels in histones 3 (AcH3) and 4 (AcH4), and the presence of RNA pol II (Ser2) in the promoter region of B7-H6 gene (Figure 2a). However, the treatment with (+) JQ1 significantly reduced the presence of both acetylated histones and of the active form of RNA pol II (Figure 2a). Moreover, B7-H6 expression was decreased in a dose-dependent manner in the presence of the CDK9 kinase activity inhibitor, DRB (Figure 2b), confirming that BRD4 acts as a bridge between the B7-H6 promoter and the transcriptional machinery needed for its transcription.
Related Knowledge Centers
- Acetylation
- Alpha Helix
- Bromodomain
- Lysine
- Protein
- Rna Polymerase II
- Gene
- Turn
- Transcription
- P-Tefb
- Rna Polymerase II