scholarly journals Design, Synthesis and Evaluation of WD-repeat containing protein 5 (WDR5) degraders

2021 ◽  
Author(s):  
Anja Dölle ◽  
Bikash Adhikari ◽  
Andreas Krämer ◽  
Janik Weckesser ◽  
Nicola Berner ◽  
...  
Keyword(s):  
Scaffolding Proteins ◽  
Design Synthesis ◽  
Histone Methyltransferases ◽  
Chemically Induced ◽  
Histone H3k4 ◽  
Non Coding Rnas ◽  
Wd Repeat ◽  
Tumor Types ◽  
Oncogenic Function ◽  
Site Binding

AbstractHistone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat containing protein 5 (WDR5) that has also been associated with controlling long non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic function. This study presents the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

scholarly journals Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders

2021 ◽  
Author(s):  
Anja Dölle ◽  
Bikash Adhikari ◽  
Andreas Krämer ◽  
Janik Weckesser ◽  
Nicola Berner ◽  
...  
Keyword(s):  
Design Synthesis ◽  
Wd Repeat

scholarly journals The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 921
Author(s):  
Ekaterina Mikhailovna Stasevich ◽  
Matvey Mikhailovich Murashko ◽  
Lyudmila Sergeevna Zinevich ◽  
Denis Eriksonovich Demin ◽  
Anton Markovich Schwartz
Keyword(s):  
Malignant Tumors ◽  
Current Data ◽  
Cellular Processes ◽  
Cell Divisions ◽  
Specific Tumor ◽  
Different Types ◽  
Myc Gene ◽  
Non Coding Rnas ◽  
Tumor Types

Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.

scholarly journals LINC00885 promotes cervical cancer progression through sponging miR-3150b-3p and upregulating BAZ2A

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Yeling Liu ◽  
Jingrui Chen ◽  
Lizhong Zhou ◽  
Chunhua Yin
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Animal Experiments ◽  
Cell Behaviors ◽  
Protein Levels ◽  
Non Coding Rna ◽  
Promising Therapeutic Target ◽  
Proliferation And Apoptosis ◽  
Non Coding Rnas ◽  
Oncogenic Function

Abstract Background Cervical cancer (CC) is one of the most common malignancies affecting female worldwide. Long non-coding RNAs (lncRNAs) are increasingly indicated as crucial participants and promising therapeutic targets in human cancers. The main objective of this study was to explore the functions and mechanism of LINC00885 in CC. Methods RT-qPCR and western blot were used to detect RNA and protein levels. Functional and mechanism assays were respectively done for the analysis of cell behaviors and molecular interplays. Results Long intergenic non-coding RNA 885 (LINC00885) was discovered to be upregulated in CC tissues and cell lines through bioinformatics analysis and RT-qPCR. Overexpression of LINC00885 promoted proliferation and inhibited apoptosis, whereas its silence exerted opposite effects. The cytoplasmic localization of LINC00885 was ascertained and furthermore, LINC00885 competitively bound with miR-3150b-3p to upregulate BAZ2A expression in CC cells. Rescue assays confirmed that LINC00885 regulated CC proliferation and apoptosis through miR-3150b-3p/BAZ2A axis. Finally, we confirmed that LINC00885 aggravated tumor growth through animal experiments. Conclusions LINC00885 exerted oncogenic function in CC via regulating miR-3150b-3p/BAZ2A axis. These findings suggested LINC00885 might serve as a potential promising therapeutic target for CC patients.

Design, Synthesis, and Proposed Active Site Binding Analysis of Monocyclic 2-Azetidinone Inhibitors of Prostate Specific Antigen

2001 ◽  
Vol 44 (10) ◽  
pp. 1491-1508 ◽  
Author(s):  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
Gerald W. Becker ◽  
Beining Chen ◽  
Leifeng Cheng ◽  
...  
Keyword(s):  
Prostate Specific Antigen ◽  
Active Site ◽  
Specific Antigen ◽  
Design Synthesis ◽  
Binding Analysis ◽  
Site Binding

Recent Progress in the Development of Small Molecule c-Met Inhibitors

2019 ◽  
Vol 19 (15) ◽  
pp. 1276-1288 ◽  
Author(s):  
Peng-Cheng Lv ◽  
Yu-Shun Yang ◽  
Zhong-Chang Wang
Keyword(s):  
Small Molecule ◽  
Rational Design ◽  
Antitumor Agents ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Human Tumor ◽  
Design Synthesis ◽  
Relationship Analysis ◽  
Tumor Types ◽  
Hepatocyte Growth

C-Met, also referred to as Hepatocyte Growth Factor Receptor (HGFR), is a heterodimeric receptor tyrosine kinase. It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway. Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients. The c-Met kinase has emerged as an attractive target for developing antitumor agents. In this review, we cover the recent advances on the small molecule c-Met inhibitors discovered from 2018 until now, with a main focus on the rational design, synthesis and structureactivity relationship analysis.

scholarly journals Aberrant Expression of microRNA Clusters in Head and Neck Cancer Development and Progression: Current and Future Translational Impacts

2021 ◽  
Vol 14 (3) ◽  
pp. 194
Author(s):  
Li-Jie Li ◽  
Wei-Min Chang ◽  
Michael Hsiao
Keyword(s):  
Head And Neck ◽  
Biological Functions ◽  
Aberrant Expression ◽  
Pathological Conditions ◽  
Epigenetic Events ◽  
High Sequence Conservation ◽  
Endogenous Genes ◽  
Non Coding Rnas ◽  
Disease Stages ◽  
Oncogenic Function

MicroRNAs are small non-coding RNAs known to negative regulate endogenous genes. Some microRNAs have high sequence conservation and localize as clusters in the genome. Their coordination is regulated by simple genetic and epigenetic events mechanism. In cells, single microRNAs can regulate multiple genes and microRNA clusters contain multiple microRNAs. MicroRNAs can be differentially expressed and act as oncogenic or tumor suppressor microRNAs, which are based on the roles of microRNA-regulated genes. It is vital to understand their effects, regulation, and various biological functions under both normal and disease conditions. Head and neck squamous cell carcinomas are some of the leading causes of cancer-related deaths worldwide and are regulated by many factors, including the dysregulation of microRNAs and their clusters. In disease stages, microRNA clusters can potentially control every field of oncogenic function, including growth, proliferation, apoptosis, migration, and intercellular commutation. Furthermore, microRNA clusters are regulated by genetic mutations or translocations, transcription factors, and epigenetic modifications. Additionally, microRNA clusters harbor the potential to act therapeutically against cancer in the future. Here, we review recent advances in microRNA cluster research, especially relative to head and neck cancers, and discuss their regulation and biological functions under pathological conditions as well as translational applications.

scholarly journals Cryo-EM structure of the human Mixed Lineage Leukemia-1 complex bound to the nucleosome

2019 ◽  
Author(s):  
Sang Ho Park ◽  
Alex Ayoub ◽  
Young Tae Lee ◽  
Jing Xu ◽  
Hanseong Kim ◽  
...  
Keyword(s):  
Mixed Lineage Leukemia ◽  
Chromatin Binding ◽  
Histone H4 ◽  
Core Complex ◽  
Regulate Gene Expression ◽  
Histone Methyltransferases ◽  
Nucleosome Core ◽  
Nucleosomal Dna ◽  
Histone H3k4 ◽  
Methylation Activity

SUMMARYMixed Lineage Leukemia (MLL) family histone methyltransferases are the key enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanism by which the MLL complexes recognize histone H3K4 within the nucleosome core particle (NCP) remains unclear. Here, we report the single-particle cryo-electron microscopy (cryo-EM) structure of the human MLL1 core complex bound to the NCP. The MLL1 core complex anchors on the NCP through RbBP5 and ASH2L, which interacts extensively with nucleosomal DNA as well as the surface close to histone H4 N-terminal tail. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, allowing symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

Sign in / Sign up

Export Citation Format

Share Document