scholarly journals Inhibitors in AKTion: ATP-competitive vs allosteric

2020 ◽  
Vol 48 (3) ◽  
pp. 933-943
Author(s):  
Glorianne Lazaro ◽  
Eleftherios Kostaras ◽  
Igor Vivanco
Keyword(s):  
Therapeutic Target ◽  
Human Cancer ◽  
Pi3k Pathway ◽  
Clinical Development ◽  
Future Prospects ◽  
Therapeutic Targeting ◽  
Human Tumours ◽  
Drug Classes ◽  
Context Specific ◽  
Oncogenic Function

Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target. Multiple AKT inhibitors, broadly classified as either ATP-competitive or allosteric, are currently in various stages of clinical development. Herein, we review the evidence for AKT dependence in human tumours and focus on its therapeutic targeting by the two drug classes. We highlight the future prospects for the development and implementation of more effective context-specific AKT inhibitors aided by our increasing knowledge of both its regulation and some previously unrecognised non-canonical functions.

scholarly journals EZH2 as a new therapeutic target in brain tumors: Molecular landscape, therapeutic targeting and future prospects

2022 ◽  
Vol 146 ◽  
pp. 112532
Author(s):  
Mahshid Deldar Abad Paskeh ◽  
Atefeh Mehrabi ◽  
Mohammad Hossein Gholami ◽  
Amirhossein Zabolian ◽  
Ehsan Ranjbar ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Therapeutic Target ◽  
Future Prospects ◽  
Therapeutic Targeting ◽  
Molecular Landscape

CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTS

2005 ◽  
Vol 45 (1) ◽  
pp. 495-528 ◽  
Author(s):  
Daryl C. Drummond ◽  
Charles O. Noble ◽  
Dmitri B. Kirpotin ◽  
Zexiong Guo ◽  
Gary K. Scott ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Clinical Development ◽  
Clinical Activity ◽  
Innovative Drug ◽  
Nonhistone Proteins ◽  
Drug Classes

Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.

ADAMTS9-AS2: A functional long non-coding RNA in tumorigenesis

2021 ◽  
Vol 27 ◽  
Author(s):  
Wen Xu ◽  
Bei Wang ◽  
Yuxuan Cai ◽  
Jinlan Chen ◽  
Xing Lv ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Signaling Pathways ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Migration Inhibition ◽  
Cancer Proliferation ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Background: Long non-coding RNAs (lncRNA) have been identified as novel molecular regulators in cancers. LncRNA ADAMTS9-AS2 can mediate the occurrence and development of cancer through various ways such as regulating miRNAs, activating the classical signaling pathways in cancer, and so on, which have been studied by many scholars. In this review, we summarize the molecular mechanisms of ADAMTS9-AS2 in different human cancers. Methods: Through a systematic search of PubMed, lncRNA ADAMTS9-AS2 mediated molecular mechanisms in cancer are summarized inductively. Results: ADAMTS9-AS2 aberrantly expression in different cancers is closely related to cancer proliferation, invasion, migration, inhibition of apoptosis. The involvement of ADAMTS9-AS2 in DNA methylation, mediating PI3K / Akt / mTOR signaling pathways, regulating miRNAs and proteins, and such shows its significant potential as a therapeutic cancer target. Conclusion: LncRNA ADAMTS9-AS2 can become a promising biomolecular marker and a therapeutic target for human cancer.

Dysregulation of miRNA in cancer progression

2021 ◽  
Author(s):  
Rucha P.
Keyword(s):  
Gene Regulation ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Chromosomal Abnormalities ◽  
Human Cancer ◽  
Epigenetic Modification ◽  
Therapeutic Applications ◽  
Non Coding Rnas ◽  
Transcriptional Gene Regulation

MicroRNAs (miRNAs) are a category of highly conserved tiny non-coding RNAs that play a role in post-transcriptional gene regulation. Numerous studies have shown the role of dysregulated miRNA in a variety of illnesses, including human cancer. MiRNA is dysregulated by a variety of processes, including dysregulation of miRNA synthesis, aberrant miRNA transcription, dysregulated epigenetic modification, and chromosomal abnormalities. MiRNAs that are overexpressed have been shown to influence cancer's hallmarks. Recent research has shown miRNA's potential as a therapeutic target and biomarker. In this review, we discussed the synthesis and regulation of miRNA, as well as its dysregulation in human cancer and other disorders, as well as some of the therapeutic applications of miRNA.

scholarly journals Characterising Mutational Spectra of Carcinogens in the Tumour Suppressor Gene TP53 Using Human TP53 Knock-in (Hupki) Mouse Embryo Fibroblasts

2019 ◽  
Vol 2 (4) ◽  
pp. 85 ◽  
Author(s):  
Hölzl-Armstrong ◽  
Kucab ◽  
Korenjak ◽  
Luijten ◽  
Phillips ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Human Cancer ◽  
Atmospheric Oxygen ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
International Agency ◽  
Human Tumours ◽  
Clonal Cell Lines ◽  
Gene Tp53

DNA in dividing cells is prone to mutagenesis, with mutations making key contributions to human disease including cancer. The tumour suppressor gene TP53 is the most frequently mutated gene in human tumours. Here, we present a robust protocol for studying TP53 mutagenesis utilising human TP53 knock-in (Hupki) mouse embryonic fibroblasts (HUFs). In the HUF immortalisation assay (HIMA), primary HUFs are treated with known or suspected carcinogens at 3% oxygen and then transferred to 20% atmospheric oxygen to induce senescence. Cells containing mutations (e.g., in TP53) that allow bypassing of senescence eventually emerge as immortalised clonal cell lines after 2–3 months of serial passaging. As not all immortalised HUF cells contain TP53 mutations, we developed a Nutlin-3a counter-screen to select for TP53-mutated clones prior to sequencing. TP53 mutation spectra generated can be compared with those of human tumours recorded in the International Agency for Research on Cancer TP53 mutation database. Environmental mutagens that have demonstrated and validated the utility of the HIMA include ultraviolet radiation, aristolochic acid, and benzo[a]pyrene. The TP53 mutation patterns induced by these mutagens in the HIMA corresponded to those found in human tumours from patients exposed to these mutagens. The approach presented helps to deepen our understanding of human cancer aetiology.

scholarly journals Cracking the context-specific PI3K signaling code

2020 ◽  
Vol 13 (613) ◽  
pp. eaay2940 ◽  
Author(s):  
Ralitsa R. Madsen ◽  
Bart Vanhaesebroeck
Keyword(s):  
Current Knowledge ◽  
Computer Software ◽  
Normal Growth ◽  
Pi3k Pathway ◽  
Primary Immune Deficiency ◽  
Pi3k Signaling ◽  
Environmental Signals ◽  
Technological Advances ◽  
Context Dependent ◽  
Context Specific

Specificity in signal transduction is determined by the ability of cells to “encode” and subsequently “decode” different environmental signals. Akin to computer software, this “signaling code” governs context-dependent execution of cellular programs through modulation of signaling dynamics and can be corrupted by disease-causing mutations. Class IA phosphoinositide 3-kinase (PI3K) signaling is critical for normal growth and development and is dysregulated in human disorders such as benign overgrowth syndromes, cancer, primary immune deficiency, and metabolic syndrome. Despite decades of PI3K research, understanding of context-dependent regulation of the PI3K pathway and of the underlying signaling code remains rudimentary. Here, we review current knowledge on context-specific PI3K signaling and how technological advances now make it possible to move from a qualitative to quantitative understanding of this pathway. Insight into how cellular PI3K signaling is encoded or decoded may open new avenues for rational pharmacological targeting of PI3K-associated diseases. The principles of PI3K context-dependent signal encoding and decoding described here are likely applicable to most, if not all, major cell signaling pathways.

scholarly journals Down-regulation of the Tumor Suppressor C-terminal Src Kinase (Csk)-binding Protein (Cbp)/PAG1 Is Mediated by Epigenetic Histone Modifications via the Mitogen-activated Protein Kinase (MAPK)/Phosphatidylinositol 3-Kinase (PI3K) Pathway

2011 ◽  
Vol 286 (18) ◽  
pp. 15698-15706 ◽  
Author(s):  
Kei Suzuki ◽  
Chitose Oneyama ◽  
Hironobu Kimura ◽  
Shoji Tajima ◽  
Masato Okada
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Histone Modifications ◽  
Human Cancer ◽  
Methylation Status ◽  
Adaptor Protein ◽  
Pi3k Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Down Regulation ◽  
Human Cancer Cells

The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression. The levels of Cbp expression were inversely correlated with the activity of MEK and Akt, and Cbp down-regulation was suppressed by inhibiting MEK and PI3K. Src transformation did not affect the stability of Cbp mRNA, the transcriptional activity of the cbp promoter, or the DNA methylation status of the cbp promoter CpG islands. However, Cbp expression was restored by treatment with histone deacetylase (HDAC) inhibitors and by siRNA-mediated knockdown of HDAC1/2. Src transformation significantly decreased the acetylation levels of histone H4 and increased the trimethylation levels of histone H3 lysine 27 in the cbp promoter. EGF-induced Cbp down-regulation was also suppressed by inhibiting MEK and HDAC. Furthermore, the inhibition of MEK or HDAC restored Cbp expression in human cancer cells harboring Cbp down-regulation through promoter hypomethylation. These findings suggest that Cbp down-regulation is primarily mediated by epigenetic histone modifications via oncogenic MAPK/PI3K pathways in a subset of cancer cells.

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