Hes1 inhibitor isolated by target protein oriented natural products isolation (TPO-NAPI) of differentiation activators of neural stem cells

Arai, Midori A.; Ishikawa, Naoki; Tanaka, Mitsuha; Uemura, Kenji; Sugimitsu, Noriko; Suganami, Akiko; Tsutsumi, Yutaka; Koyano, Takashi; Kowithayakorn, Thaworn; Ishibashi, Masami

doi:10.1039/c5sc03540f

Cited by 26 publications

(28 citation statements)

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“…Inhibition of Hes1 by small molecules, and in vivo delivery of Hes1 siRNA, are two approaches that can be employed to target Hes1 for therapeutic purposes. Several compounds can inhibit Hes1 activity (38)(39)(40). Agalloside, which directly binds to Hes1, has been recently identified as a naturally occurring Hes1 dimer inhibitor (39).…”

Section: Discussionmentioning

confidence: 99%

Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine

et al. 2017

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Cancer stem cells (CSC) have attracted attention as therapeutic targets; however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here, we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSCs and intestinal tumors. Lineage-tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5 or Bmi1 NSCs resulted in loss of self-renewal but did not perturb homeostasis. Furthermore, in Lgr5 NSC, deletion of Hes1 and β-catenin stabilization limited tumor formation and prolonged host survival. Notably, in Lgr5 or Dclk1 tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSCs and CSCs, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target. .

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Section: Discussionmentioning

confidence: 99%

Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine

et al. 2017

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“…This compound was isolated by the "target protein oriented natural products isolation" (TPO-NAPI) method using the Hes1-immobilized beads constructed in our group. 41) Hes1 belongs to repressor-type bHLH proteins and inhibits the expression of activator-type bHLH factors. Therefore, Hes1 inhibitors are expected to accelerate neural stem cell differentiation.…”

Section: Acridine and Hydroxypiperidine Derivativesmentioning

confidence: 99%

Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species

2016

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Natural products from actinomycetes are important and valuable sources for drug discovery and the development of biological tools. The present review describes our recent study on the isolation of new natural products mainly possessing heterocyclic and aromatic ring structures with biological effects on cancerrelated cellular pathways such as tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) and Wnt signaling.

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“…2B). Agalloside, inohanamine, α-mangostine, BE-14106, isomicromonolactam, staurosporin and linarin were isolated as Hes1 binding compounds using the TPO-NAPI method 15,17 . Rat Hes1 (1-95) containing basic and helix-loop-helix domains was immobilized because the helix-loop-helix domain is known to be important for Hes1-Hes1 interaction; therefore, utilizing this domain in the beads method would likely be effective for screening Hes1 dimer inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…In our attempts to find Hes1 inhibitors effectively, we constructed a new Hes1-Hes1 interaction fluorescent plate assay which gave the first Hes1 dimer inhibitors 24 . Also, we have developed "target protein oriented natural products isolation (TPO-NAPI) methods" using protein-immobilized beads 11,15,17,18 . Lindbladione 15 , agalloside 15 , isomicromonolactam 17 and inohanamine 17 were isolated by using Hes1 protein beads and accelerated the differentiation of NSCs to neurons.…”

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Target protein-oriented isolation of Hes1 dimer inhibitors using protein based methods

Arai

Morita

Kawano

et al. 2020

Sci Rep

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Natural products isolation using protein based methods is an attractive for obtaining bioactive compounds. To discover neural stem cell (NSC) differentiation activators, we isolated eight inhibitors of Hes1 dimer formation from Psidium guajava using the Hes1-Hes1 interaction fluorescent plate assay and one inhibitor from Terminalia chebula using the Hes1-immobilized beads method. Of the isolated compounds, gallic acid (8) and 4-O-(4"-O-galloyl-α-L-rhamnopyranosyl)ellagic acid (11) showed potent Hes1 dimer formation inhibitory activity, with IC 50 values of 10.3 and 2.53 μM, respectively. Compound 11 accelerated the differentiation activity of C17.2 NSC cells dose dependently, increasing the number of neurons with a 125% increase (5 μM) compared to the control.Neurodegenerative diseases such as dementia and spinal cord injury severely compromise the quality of life. The discovery of neural stem cells (NSCs) in human adult brain 1,2 led to the expectation of novel treatments involving NSC transplantation or accelerated differentiation of internal NSCs in the brain to overcome neurodegenerative diseases. However, the development of these approaches and small molecule NSC activators has been slow, possibly due to the complex mechanism underlying the differentiation of NSCs to neural cells.Basic helix-loop-helix (bHLH) factors play crucial roles in the differentiation of neural cells such as neurons, astrocytes and oligodendrocytes 3 . For example, proneural bHLH factors, such as Ascl1 (formerly Mash1), Neurog1 and Neurog2 regulate the generation of neurons. Olig1 and Olig2 are bHLH factors important for the maturation of oligodendrocytes. Hairy and enhancer of split (hes) bHLH factors promote the self-renewal of NSCs and the generation of astrocytes, as well as inhibiting the differentiation of NSCs by suppressing the expression of proneural genes. Recently, Kageyama et al. reported that oscillation in the concentration of bHLH factors directly controls the fate of NSCs 4,5 . Hes1 and Ascl1 proteins oscillate with 2-to 3-hour periods, whereas Olig2 oscillates with a 5-to 8-hour period. During cell fate choice, one bHLH factor is expressed in a sustained manner while the others are repressed. In neurons, Ascl1 is expressed sustainably while Hes1 and Olig2 expression is inhibited.Hes1 dimerizes and binds to the promoter region of Ascl1 and other proneural genes (Fig. 1), making the inhibition of Hes1 an attractive approach to enhance neuronal differentiation. If the interested target protein was decided, it would be faster and effective to isolate the bioactive natural products using a "protein-based assay system" 6 . However, the number of reports of isolation using protein-based assay system was still limited (affinity chromatography 7-9 , protein-immobilized beads 10-18 , ultrafiltration 19-21 , and protein-protein interactions 22,23 ). In our attempts to find Hes1 inhibitors effectively, we constructed a new Hes1-Hes1 interaction fluorescent plate assay which gave the first Hes1 dimer inhibitors 24 . Also, we have...

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Hes1 inhibitor isolated by target protein oriented natural products isolation (TPO-NAPI) of differentiation activators of neural stem cells

Abstract: Hes1 dimer inhibitor, agalloside (2), which can accelerate the differentiation of neural stem cells was isolated by using Hes1-immobilized beads.

Cited by 26 publications

References 58 publications

Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine

Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine

Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species

Target protein-oriented isolation of Hes1 dimer inhibitors using protein based methods

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