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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
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].
Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
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).
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
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.
BET inhibitors: an updated patent review (2018–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Huanhuan Chen, Zhenling Liu, Lili Zheng, Rongrong Wang, Lei Shi
BRD4 has three expression forms including one long isoform (1362 residues) and two short isoforms (722 and 796 residues). All these isoforms are expressed in many different types of human cells. In addition to the two BD domains and one ET domain, the long isoform BRD4 also has a carboxy-terminal domain (CTD) at the end. CTD recruits positive transcriptional extensions (P-TEFb) to the acetylated histone gene transcription regions of the BRD4 target genes Cyclin T1 and CDK9, activates transcriptional initial response genes, and recruits P-TEFb complexes to phosphorylate RNA polymerase II (PolII), restore transcription extension and promote transcription [7]. The BET domain interacts with a variety of transcriptional regulators, such as histone arginine methylase (JMJD6) and chromatin DNA uncoiling DNA binding protein (CHD4), and plays an important role in transcription regulation [8]. BRD4 can recognize not only acetylated histones but also acetylated non-histone proteins, such as NF-κB subunit RelA, which participate in biological processes such as inflammation and oxidative stress.
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.
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
The bromodomain (BRD) and extra-terminal (BET) family of proteins recruit transcriptional regulatory complexes to acetylated, transcriptionally permissive chromatin [100]. The C-terminal positive transcription elongation factor b (pTEFb), a heterodimer composed of cyclin T and CDK9, binds to BRD4 protein and regulates activity of RNA polymerase II. BRD4 thus couples histone acetylation to transcription. BET protein bromodomain antagonists (BA) demonstrated promising anti-tumor activity in a wide range of malignancies. Displacement of BRD4 and pTEFb from the acetylated chromatin decreases transcription of key oncogenes (e.g. MYC, CCND1, CDK4, and BCL2) and genes involved in BCR signaling (e.g. B-cell linker protein, PAX5, IKZF3) [101]. The inhibitors also block aberrant activation of NFkappaB and have shown promising anti-lymphoma activity in bortezomib or ibrutinib-resistant MCL [102–105].