Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

Das, Nando Dulal; Niwa, Hideaki; Umehara, Takashi

doi:10.3390/epigenomes7010007

Cited by 12 publications

(4 citation statements)

References 139 publications

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“…Interestingly, KDM3A also appears to regulate specific DCLK1 isoforms, suggesting a deeper connection between histone modifications and isoform control [117]. With KDM3A being a promising therapeutic target, its inhibitors are currently under development (reviewed in Das et al [118]).…”

Section: The Interplay Of Gene Isoforms Epigenetics and Cancer Stem C...mentioning

confidence: 99%

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

Moore,

Houchen

2023

IJMS

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While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1.

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Section: The Interplay Of Gene Isoforms Epigenetics and Cancer Stem C...mentioning

confidence: 99%

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

Moore,

Houchen

2023

IJMS

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“…[28][29][30][31][32][33] These molecules have been shown to play a significant role in the regulation of gene expression, which is linked to the development of various human cancers and other diseases. [34][35][36][37][38][39] In recent years, there has been a significant effort to utilize chemical and biochemical tools to influence intracellular pathways and thereby manipulate the behavior of cells and organisms. [40][41] However, once the cargos (small organic molecules, proteins, nucleic acids, bioconjugates, etc.)…”

Section: Introductionmentioning

confidence: 99%

A Live-Cell Epigenome Manipulation by Photo-stimuli-responsive Histone Methyltransferase Inhibitor

Wu,

Sun,

Liu

et al. 2024

Preprint

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Post-translational modifications (PTMs) on the histone H3 tail regulate chromatin structure and impact epigenetics and hence the gene expressions. Current chemical modulation tools, such as unnatural amino acid incorporation, protein splicing, and sortase-based editing, have allowed for the modification of histones with various PTMs in cellular contexts, but most of these methods are not applicable for editing native chromatin. The use of small organic molecules to manipulate histone-modifying enzymes alters endogenous histone PTMs but lacks precise temporal and spatial control. To date, there has been no achievement in modulating biologically significant histone methylation in living cells with spatiotemporal resolution. In this study, we present a new method for temporally editing dimethylation H3K9me2 using a photo-responsive inhibitor that specifically targets the histone methyltransferase G9a upon light irradiation. The photo-caged molecule was stable under physiological conditions and in cellular environments, but rapidly decomposed upon exposure to light, releasing the bioactive component that can immediately inhibit the catalytic ability of the G9a in vitro. Besides, this masked compound could also efficiently promote the inhibition of methyltransferase activity in living cells, subsequently suppress H3K9me2, a mark that regulates various chromatin functions. Therefore, our chemical system will be a valuable tool for manipulating the epigenome for therapeutic purposes and furthering the understanding of epigenetic mechanisms.

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“…26,27) Therefore, LSD1 inhibitors are of interest both as tools for studying LSD1 functions and as potential therapeutic agents. [28][29][30][31][32][33][34] Thus far, many LSD1 inhibitors have been reported. [28][29][30][31][32][33][34] However, most of these inhibitors are small molecules, and peptide-based inhibitors are relatively scarce.…”

Section: Introductionmentioning

confidence: 99%

“…[28][29][30][31][32][33][34] Thus far, many LSD1 inhibitors have been reported. [28][29][30][31][32][33][34] However, most of these inhibitors are small molecules, and peptide-based inhibitors are relatively scarce. 12,[35][36][37][38][39][40][41][42][43][44][45][46] A series of the reported peptide-based LSD1 inhibitors were designed based on SNAIL1, 17,[43][44][45][46][47] a member of the SNAIL/SCRATCH family of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

A Structure–Activity Relationship Study of SNAIL1 Peptides as Inhibitors of Lysine-Specific Demethylase 1

Takada,

Adachi,

Fujinaga

et al. 2024

CHEMICAL & PHARMACEUTICAL BULLETIN

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Peptides have recently garnered attention as middle-molecular-weight drugs with the characteristics of small molecules and macromolecules. Lysine-specific demethylase 1 (LSD1) is a potential therapeutic target for lung cancer, neuroblastoma, and leukemia, and some peptide-based LSD1 inhibitors designed based on the N-terminus of SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors, have been reported. The N-terminus of SNAIL1 peptide acts as a cap of the catalytic site of LSD1, inhibiting interactions with LSD1. However, the structure-activity relationship (SAR) of these inhibitors is not yet fully understood. Therefore, in the present study, we aimed to uncover the SAR and to identify novel SNAIL1 peptide-based LSD1 inhibitors. We synthesized peptide inhibitor candidates based on truncating the Nterminus of SNAIL1 or substituting its amino acid residues. In the truncation study, we found that SNAIL1 1-16 (2), which was composed of 16 residues, strongly inhibited LSD1. Furthermore, we investigated the SAR at residues-3 and -5 from the N-terminus and found that peptides 2j and 2k, in which leucine 5 of the parent peptide is substituted with unnatural amino acids, cyclohexylalanine and norleucine, respectively, strongly inhibited LSD1. This result suggests that the hydrophobic interaction between the inhibitor peptides and LSD1 affects the LSD1-inhibitory activity. We believe that this SAR information provides a basis for the development of more potent LSD1 inhibitors.

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Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

Cited by 12 publications

References 139 publications

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

A Live-Cell Epigenome Manipulation by Photo-stimuli-responsive Histone Methyltransferase Inhibitor

A Structure–Activity Relationship Study of SNAIL1 Peptides as Inhibitors of Lysine-Specific Demethylase 1

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