Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons.

ABSTRACT: The fat mass and obesity-associated protein (FTO), an RNA N⁶-methyladenosine (m⁶A) demethylase, is an important regulator of central nervous system development, neuronal signaling and disease. We present here the target-tailored development and biological characterization of small-molecule inhibitors of FTO. The active compounds were identified using high-throughput molecular docking and molecular dynamics screening of the ZINC compound library. In FTO binding and activity-inhibition assays the two best inhibitors demonstrated K_d = 185 nM; IC₅₀ = 1.46 µM (compound 2) and K_d = 337 nM; IC₅₀ = 28.9 µM (compound 3). Importantly, the treatment of mouse midbrain dopaminergic neurons with the compounds promoted cellular survival and rescued them from growth factor deprivation induced apoptosis already at nanomolar concentrations. Moreover, both the best inhibitors demonstrated good blood-brain-barrier penetration in the model system, 31.7% and 30.8%, respectively. The FTO inhibitors demonstrated increased potency as compared to our recently developed ALKBH5 m⁶A demethylase inhibitors in protecting dopamine neurons. Inhibition of m⁶A RNA demethylation by small-molecule drugs, as presented here, has therapeutic potential and provides tools for the identification of disease-modifying m⁶A RNAs in neurogenesis and neuroregeneration. Further refinement of the lead compounds identified in this study can also lead to unprecedented breakthroughs in the treatment of neurodegenerative diseases.

SUBMITTER: Selberg S

PROVIDER: S-EPMC8123663 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

FTO: linking m6A demethylation to adipogenesis.

Project description:Polymorphism of the FTO gene encoding an N(6)-methyladenosine (m(6)A) RNA demethylase was robustly associated with human obesity; however, the mechanism by which FTO affects metabolism, considering its emerging role in RNA modification, is still poorly understood. A new study published in Cell Research reports novel functions implicating FTO in the regulation of mRNA alternative splicing in the control of adipogenesis.

| S-EPMC4650590 | biostudies-other

Recent Advances of m6A Demethylases Inhibitors and Their Biological Functions in Human Diseases.

Project description:N6-methyladenosine (m6A) is a post-transcriptional RNA modification and one of the most abundant types of RNA chemical modifications. m6A functions as a molecular switch and is involved in a range of biomedical aspects, including cardiovascular diseases, the central nervous system, and cancers. Conceptually, m6A methylation can be dynamically and reversibly modulated by RNA methylation regulatory proteins, resulting in diverse fates of mRNAs. This review focuses on m6A demethylases fat-mass- and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), which especially erase m6A modification from target mRNAs. Recent advances have highlighted that FTO and ALKBH5 play an oncogenic role in various cancers, such as acute myeloid leukemias (AML), glioblastoma, and breast cancer. Moreover, studies in vitro and in mouse models confirmed that FTO-specific inhibitors exhibited anti-tumor effects in several cancers. Accumulating evidence has suggested the possibility of FTO and ALKBH5 as therapeutic targets for specific diseases. In this review, we aim to illustrate the structural properties of these two m6A demethylases and the development of their specific inhibitors. Additionally, this review will summarize the biological functions of these two m6A demethylases in various types of cancers and other human diseases.

| S-EPMC9144293 | biostudies-literature

Small molecule epigenetic inhibitors targeted to histone lysine methyltransferases and demethylases.

Project description:Altered chromatin structures and dynamics are responsible for a range of human malignancies, among which the status of histone lysine methylation remains of paramount importance. Histone lysine methylation is maintained by the relative activities of sequence-specific methyltransferase (KMT) writers and demethylase (KDM) erasers, with aberrant enzymatic activities or expression profiles closely correlated with multiple human diseases. Hence, targeting these epigenetic enzymes should provide a promising avenue for pharmacological intervention of aberrantly marked sites within the epigenome. Here we present an up-to-date critical evaluation on the development and optimization of potent small molecule inhibitors targeted to histone KMTs and KDMs, with the emphasis on contributions of structural biology to development of epigenetic drugs for therapeutic intervention. We anticipate that ongoing advances in the development of epigenetic inhibitors should lead to novel drugs that site-specifically target KMTs and KDMs, key enzymes responsible for maintenance of the lysine methylation landscape in the epigenome.

| S-EPMC4696758 | biostudies-literature

A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo.

Project description:Parkinson's disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood-brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug.

| S-EPMC9738927 | biostudies-literature

Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors.

Project description:The RNA 6-N-methyladenosine (m6A) demethylase ALKBH5 has been shown to be oncogenic in several cancer types, including leukemia and glioblastoma. We present here the target-tailored development and first evaluation of the antiproliferative effects of new ALKBH5 inhibitors. Two compounds, 2-[(1-hydroxy-2-oxo-2-phenylethyl)sulfanyl]acetic acid (3) and 4-{[(furan-2-yl)methyl]amino}-1,2-diazinane-3,6-dione (6), with IC50 values of 0.84 μM and 1.79 μM, respectively, were identified in high-throughput virtual screening of the library of 144 000 preselected compounds and subsequent verification of hits in an m6A antibody-based enzyme-linked immunosorbent assay (ELISA) enzyme inhibition assay. The effect of these compounds on the proliferation of selected target cancer cell lines was then measured. In the case of three leukemia cell lines (HL-60, CCRF-CEM, and K562) the cell proliferation was suppressed at low micromolar concentrations of inhibitors, with IC50 ranging from 1.38 to 16.5 μM. However, the effect was low or negligible in the case of another leukemia cell line, Jurkat, and the glioblastoma cell line A-172. These results demonstrate the potential of ALKBH5 inhibition as a cancer-cell-type-selective antiproliferative strategy.

| S-EPMC8158789 | biostudies-literature

Small molecule blockers of the Alzheimer Abeta calcium channel potently protect neurons from Abeta cytotoxicity.

Project description:Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (Abeta). We have hypothesized that the intrinsic Abeta calcium channel activity of the oligomeric Abeta polymer may be responsible for the neurotoxic properties of Abeta, and that Abeta channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the Abeta channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the Abeta channel and protect neurons from Abeta toxicity. Both block the Abeta channel with similar potency (approximately 500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.

| S-EPMC2637905 | biostudies-literature

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B.

Project description:Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these enzymes are potential therapeutic targets. Methods: In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation). Results: we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors.

| S-EPMC6540222 | biostudies-literature

N<sup>6</sup>-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury.

Project description:BackgroundAlthough N6-methyladenosine (m6A) plays a very important role in different biological processes, its function in the brain has not been fully explored. Thus, we investigated the roles of the RNA demethylases Alkbh5/Fto in cerebral ischemia-reperfusion injury.MethodsWe used a rat model and primary neuronal cell culture to study the role of m6A and Alkbh5/Fto in the cerebral cortex ischemic penumbra after cerebral ischemia-reperfusion injury. We used Alkbh5-shRNA and Lv-Fto (in vitro) to regulate the expression of Alkbh5/Fto to study their regulation of m6A in the cerebral cortex and to study brain function after ischemia-reperfusion injury.ResultsWe found that RNA m6A levels increased consecutive to the increase of Alkbh5 expression in both the cerebral cortex of rats after middle cerebral artery occlusion, and in primary neurons after oxygen deprivation/reoxygenation. In contrast, Fto expression decreased after these perturbations. Our results suggest that knocking down Alkbh5 can aggravate neuronal damage. This is due to the demethylation of Alkbh5 and Fto, which selectively demethylate the Bcl2 transcript, preventing Bcl2 transcript degradation and enhancing Bcl2 protein expression.ConclusionCollectively, our results demonstrate that the demethylases Alkbh5/Fto co-regulate m6A demethylation, which plays a crucial role in cerebral ischemia-reperfusion injury. The results provide novel insights into potential therapeutic mechanisms for stroke.

| S-EPMC7222229 | biostudies-literature

Inhibitors of Protein Methyltransferases and Demethylases.

Project description:Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

| S-EPMC5610952 | biostudies-literature

Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5.

Project description:Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N(6)-methyladenosine (m(6)A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m(6)A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.

| S-EPMC4288171 | 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