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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].
Applications of Nanoparticles in the Treatment of Gliomas
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Gerardo Caruso, Elena Fazzari, Salvator M. Cardali, Maria Caffo
Nanotechnology has notably changed the classical modality in which diagnosis and treatment are achieved mainly due to recent advances in material engineering, drug availability, and the targeting of cancer cells. As already reported, the mechanism of RMT, through binding to specific receptors placed on endothelial and tumor cells, allows the passage of pharmacological compounds through the BBB. Tf-Rs are overexpressed in brain capillary endothelium and glioma cells. Paclitaxel can inhibit cell division via promoting the gathering and stabilization of microtubules. In a recent study, the compound formed by Tf-conjugated magnetic silica PLGA NPs (MNPMSN-PLGA-Tf NPs) loaded with doxorubicin (DOX) and paclitaxel (PTX) (DOX-PTX-NPs-Tf) was evaluated. The cellular uptake of DOX-PTX-NPs-Tf could be enhanced by the presence of magnetic field and the usage of Tf as the targeting ligand; moreover, it showed a significant inhibition of tumor growth [70]. In a recent experimental study, a compound characterized by a transferrin-functionalized PEGylated NPs (Tf-NPs) able to carry TMZ and the bromodomain inhibitor JQ1 was tested. In two intracranial orthotopic mouse models of GBM, the authors demonstrated decreased tumor burden and prolonged survival [45]. It has been reported that low density LRP are overexpressed on BBB and on glioma cells. Conjugation of NPs with angiopep (ANG1005 consists of a 19 amino acid long peptide carrier conjugated to a taxane) is associated with improved delivery of the compound across the BBB via lipoprotein receptor-mediated endocytosis. An interesting research showed a notable penetration and accumulation of ANG-PEG-NP-PTX into 3D glioma spheroids and in gliomas in vivo. The efficacy of PTX loading ANG-PEG-NP was also significantly enhanced [71].
Role of Epigenetics in Immunity and Immune Response to Vaccination
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Recent studies have shown that epigenetic mechanisms are crucial for development of immune cells (Busslinger and Tarakhovsky 2014). One such study is conducted by Komori et al. where they identified a methylation signature associated with 39 upregulated and hypomethylated genes. This methylation signature is unique to memory CD4 cells and correlates with activation-induced gene expression (Komori et al. 2015). Similar findings have also been obtained by additional studies, where it was shown that related orphan receptor C, P‑selectin, and E‑selectin genes were hypomethylated in CD4+ memory T cells, in contrast to their hypermethylated states in naive CD4+ T cells (Syrbe et al. 2004; Schmidl et al. 2011). Changes in DNA methylation patterns are also observed in CD8+ T cells during differentiation to memory cells in certain genes after exposure to viral antigens (Youngblood et al. 2011). Evidently alterations to chromatin accessibility play a key role in gene regulation in immune system. Macrophage toll-like receptor (TLR) signaling results in acetylated lysines on histones interacting with cytokine genes. This modification in turn leads to upregulation of these genes by facilitating its interaction with transcription-enhancing elements (Aung et al. 2006; Nicodeme et al. 2010). In contrast to this, a thienotriazolodiazepine derivative, JQ1, suppresses the expression of cytokines by impairing the aforementioned interaction. This suppression has been shown to confer protection against exposure to heat-killed Salmonella typhimurium in mice (Belkina et al. 2013). Direct covalent histone modifications can also have an inhibitory effect on gene expression in macrophages. Histone deacetylase 11 modifies the histone structure, giving rise to a more condensed chromatin. This condensation inhibits the interaction of transcription factors with Interleukin 10 (IL-10) gene and suppresses its expression (Villagra et al. 2009).
BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3
Published in Hematology, 2023
Li Ma, Jianwei Wang, Yang Yang, Jun Lu, Jing Ling, Xinran Chu, Zimu Zhang, Yanfang Tao, Xiaolu Li, Yuanyuan Tian, Zhiheng Li, Yongping Zhang, Xu Sang, Lihui Lu, Xiaomei Wan, Kunlong Zhang, Yanling Chen, Juanjuan Yu, Ran Zhuo, Shuiyan Wu, Jian Pan, Xiuxia Zhou, Yixin Hu, Shaoyan Hu
JQ1 is the first- generation-specific inhibitor of BET. J. Ott et al. reported that JQ1 could reduce B-ALL cell lines viability and decrease their cytogenetic risk, confirming the therapeutic potential of JQ1 in B-ALL [31]. However, the clinical application was significantly limited because of the prolonged administration-related resistance and JQ1 short half-life. The novel approach PROTACs consists of a single protein of interest (POI) bound ligand, another E3 ubiquitin ligase-recruiting ligand, and a linker that connects both. The PROTAC technology hijacks the ubiquitin-proteasome system (UPS) to degrade a POI, and in vivo degradation studies have demonstrated that PROTACs can reduce targeted protein in various tissues including solid tumors. MZ1 is the refined PROTAC that was built with E3 recruiter VH032 and a target engagement warhead JQ1. VHL is responsible for the recruitment of target proteins, and the effectively increased ubiquitin-proteasome mediated degradation of target proteins. Low concentrations of MZ1 can effectively and quickly induce reversible, persistent, and unexpected selective removal of BRD4, with a low probability of inducing adverse events (e.g. natural VHL substrate stabilization) [32]. Our study found that MZ1 can exert cytotoxic effects at a lower concentration than JQ1 and other PROTAC BRD4 inhibitor (dBET1), which is consistent with previous studies.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
The bromodomain (BDR) and extraterminal (BET) family of BRD-containing proteins affect gene transcription. They include BRD2, BRD3, BRD4, and BRDT. JQ1 is a small molecule that inhibits BET proteins by competing with BRD4, leading to reduced MYC expression and impaired malignant cell growth [90]. In preclinical models, JQ1 demonstrated reduction of MYC expression [91], synergistic effects with vincristine and venetoclax [92,93], and lower transcription of the interleukin (IL)-7 receptor [94]. ETS1, a BRD4-dependent transcription factor, cooperates with NOTCH1 and can represent an alternative target to treat NOTCH1-driven T-ALL [95]. Targeting the cyclin-dependent kinase (CDK)7 represents another potential therapeutic approach, resulting in decreased enhancer activity and epigenetic reprogramming [96], and disruption of the TAL1 super-enhancer [37]. Other BET inhibitors are under investigation including epigenetic drugs and OTX015 [97].
A patent review of BRD4 inhibitors (2013-2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Tian Lu, Wenchao Lu, Cheng Luo
In 2009, Mitsubishi Pharmaceutical Corporation disclosed a series of thienodiazepines compounds as BRD4 inhibitors [41]. Two years later, Filippakopoulos et al. identified JQ1 as the BRD4 inhibitor through high-throughput screening (HTS). Compound JQ1 (1) is the first publicly reported inhibitor of the BET protein family, and its IC50 value against BRD4 BD1 was 77 nM and the IC50 value of BRD4 BD2 was 33 nM. JQ1 could remarkably inhibit the proliferation of leukemia cells, medulloblastoma cells, and breast cancer cells through the induction of apoptosis [12]. According to the reported crystal structure, the three-position nitrogen atom of triazole can form a key hydrogen bond with N140 in the KAc recognition pocket, while the two-position nitrogen atom in the triazole forms additional water-mediated hydrogen bond with Y97 in the pocket. Since then, JQ1 has now become a widely used chemical probe for exploring the mechanism and function of BRD4. Although the half-time of JQ1 is relatively short, which hinders the further application in vivo, it works as a meaningful starting point for the subsequent medicinal chemistry optimization.