Browse
Submit Data
Databases
API
Help

Dataset Information

3 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The long journey to bring a Myc inhibitor to the clinic.

ABSTRACT: The oncogene Myc is deregulated in the majority of human tumors and drives numerous hallmarks of cancer. Despite its indisputable role in cancer development and maintenance, Myc is still undrugged. Developing a clinical inhibitor for Myc has been particularly challenging owing to its intrinsically disordered nature and lack of a binding pocket, coupled with concerns regarding potentially deleterious side effects in normal proliferating tissues. However, major breakthroughs in the development of Myc inhibitors have arisen in the last couple of years. Notably, the direct Myc inhibitor that we developed has just entered clinical trials. Celebrating this milestone, with this Perspective, we pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable.

SUBMITTER: Whitfield JR

PROVIDER: S-EPMC8240852 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A stem cell journey in ophthalmology: From the bench to the clinic.

Project description:Debilitating diseases of the eye represent a large unmet medical need potentially addressable with stem cell-based approaches. Over the past decade, the California Institute for Regenerative Medicine (CIRM) has funded and supported the translation, from early research concepts to human trials, of therapeutic stem cell approaches for dry age-related macular degeneration, retinitis pigmentosa, and limbal stem cell deficiency. This article chronicles CIRM's journey in the ophthalmology field and discusses some key challenges and questions that were addressed along the way as well as questions that remain.

| S-EPMC8641078 | biostudies-literature

Functional movement disorder: a long journey to diagnosis.

Project description:A 61-year-old man presented to a country clinic with involuntary orofacial movements and progressive cognitive decline, causing significant disability and psychosocial distress. Review of records uncovered a 7-year history of presentations to several specialties, including memory clinics, neurology, internal medicine and emergency departments, with varied symptoms, extensive complex work up and inconclusive diagnosis. Comprehensive review at our hospital highlighted inconsistent neurological signs, fluctuating cognition and psychosocial stressors, which preceded symptom onset, leading to the diagnosis of a functional movement disorder (FMD), which subsequently improved with relaxation therapy, cognitive-behavioural therapy and physiotherapy. We illustrate a variety of somatic symptoms, diagnostic clues and management outcomes for FMDs, and the importance of diagnostic criteria to minimise costly, time-consuming and ultimately unnecessary tests of exclusion.

| S-EPMC4693124 | biostudies-other

The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.

Project description:Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs.

| S-EPMC7049092 | biostudies-literature

MYC amplifications in myeloma cell lines: correlation with MYC-inhibitor efficacy.

Project description:In multiple myeloma, elevated MYC expression is related to disease initiation and progression. We found that in myeloma cell lines, MYC gene amplifications were common and correlated with MYC mRNA and protein. In primary cell samples MYC mRNA levels were also relatively high; however gene copy number alterations were uncommon. Elevated levels of MYC in primary myeloma cells have been reported to arise from complex genetic aberrations and are more common than previously thought. Thus, elevated MYC expression is achieved differently in myeloma cell lines and primary cells. Sensitivity of myeloma cell lines to the MYC inhibitor 10058-F4 correlated with MYC expression, supporting that the activity of 10058-F4 was through specific inhibition of MYC.

| S-EPMC4673192 | biostudies-literature

Structural Biology: A Century-long Journey into an Unseen World.

Project description:When the first atomic structures of salt crystals were determined by the Braggs in 1912-1913, the analytical power of X-ray crystallography was immediately evident. Within a few decades the technique was being applied to the more complex molecules of chemistry and biology and is rightly regarded as the foundation stone of structural biology, a field that emerged in the 1950s when X-ray diffraction analysis revealed the atomic architecture of DNA and protein molecules. Since then the toolbox of structural biology has been augmented by other physical techniques, including nuclear magnetic resonance spectroscopy, electron microscopy, and solution scattering of X-rays and neutrons. Together these have transformed our understanding of the molecular basis of life. Here I review the major and most recent developments in structural biology that have brought us to the threshold of a landscape of astonishing molecular complexity.

| S-EPMC4697198 | biostudies-literature

The Long Journey of Extracellular Vesicles towards Global Scientific Acclamation.

Project description:Extracellular vesicles (EVs) are a heterogeneous class of cell-derived vesicles that are responsible for eliciting a wide array of biological processes. After decades of intense investigation, the therapeutic potential of EVs will be finally explored in a series of upcoming clinical trials. EVs are rapidly changing the understanding of human physiology and will undoubtedly transform the field of medicine. The applicability of EVs as diagnostic biomarkers and treatment vectors has captured the attention of the scientific community and investors, facilitating the rapid progression of numerous EVs-based platforms. This mini-review provides an outline of the pioneering discoveries, and their respective significances, on progressing EVs toward clinical use. We focus the attention of the readers on several promising classes of EVs that hold major opportunities to translate in clinical practice. Market analysis and future challenges facing EVs-based therapies are also discussed.

| S-EPMC10460810 | biostudies-literature

Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic

Project description:BET inhibitors have been tested in several clinical trials, and despite encouraging results from preclinical cancer models, substantial clinical benefit in monotherapy has been limited. An important aspect is the proper translation of preclinical observations into clinical evaluation. The clinical BET inhibitor BI 894999 was tested in mechanistic studies, assessing pathway modulation and rational drug combinations at clinically achievable concentrations. We used NUT carcinoma (NC) cell lines with bona fide oncogenic drivers fusions including BRD4-NUT and BRD3-NUT. Proliferation assays, pathway modulation studies, and in vivo xenografts were performed with BI 894999, in monotherapy, and in combination with the clinical p300/CBP inhibitor CCS1477. Detachment of the BET complex from chromatin in vitro was assessed by LSM immunofluorescence, and by immunohistochemistry in tumour sections. Clinical findings on pathway modulation marker such as HEXIM1 and HIST2H2BF as well as human PK data were back translated to the preclinic setting. The clinical phase I scheduling regimen of 1 week-on (with a loading dose on day 1) and one week-off, derived from modelling of preclinical and clinical data, achieved plasma levels of about 20 nM. This concentration led to the full removal of BRD-NUT from chromatin and resulted in sustained and prolonged PD modulation of HEXIM1 and HIST2H2BF, accompanied with better patient tolerability. Rational combination with the p300/CBP inhibitor CCS1477 led to tumour regression in all three NC xenograft models tested. Preclinical mechanistic studies with the BET inhibitor BI 894999, back translation of clinical PK/PD data, and modelling provided guidance for an optimal clinical schedule. BI 894999 holds significant potential as a combination drug and preclinical data identified p300/CBP inhibitors as highly relevant combination partner for NUT carcinoma and beyond, pending clinical trials.

2022-06-20 | GSE183214 | GEO

The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer.

Project description:MYC is one of the most important oncogenes in cancer. Indeed, MYC is upregulated in 50-60% of all tumors. MYC overexpression can be achieved through a variety of mechanisms, including gene duplications, chromosomal translocations, or somatic mutations leading to increased MYC stability. However, recent studies have identified numerous tissue-specific noncoding enhancers of MYC that play major roles in cancer, highlighting long-range transcriptional regulation of MYC as a critical novel mechanism leading to MYC hyperactivation and as a potential target for new therapeutic strategies in the near future. Here we summarize the regions and mechanisms involved in the long-range transcriptional regulation of MYC, underscoring the relevance of MYC enhancers both in normal physiological development and in MYC-driven cancer initiation and progression.

| S-EPMC6260942 | biostudies-literature

Pharmacophore identification of c-Myc inhibitor 10074-G5.

Project description:A structure-activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1) - which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues - was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with an IC(50) of 33 ?M for disruption of the Myc-Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max-Max homodimers, with no apparent effect at 100 ?M. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still.

| S-EPMC3525812 | biostudies-literature

Arsenic trioxide sensitizes glioblastoma to a myc inhibitor.

Project description:Glioblastoma multiforme (GBM) is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC) of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs) than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.

| S-EPMC4454553 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data