Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

Epigenetic dysregulation has been implicated in a variety of pathological processes including carcinogenesis. A major group of enzymes that influence epigenetic modifications are lysine demethylases (KDMs) also known as “erasers” which remove methyl groups on lysine (K) amino acids of histones. Numerous studies have implicated aberrant lysine demethylase activity in a variety of cancers, including melanoma. This review will focus on the structure, classification and functions of KDMs in normal biology and the current knowledge of how KDMs are deregulated in cancer pathogenesis, emphasizing our interest in melanoma. We highlight the current knowledge gaps of KDMs in melanoma pathobiology and describe opportunities to increases our understanding of their importance in this disease. We summarize the progress of several pre-clinical compounds that inhibit KDMs and represent promising candidates for further investigation in oncology.

show abstract

“…KDM8 demethylase target H3K36me3 inducing gene activation. Figure is adapted from Verde et al (2017). (Huang et al, 2015).…”

Section: Kdm2/3 Demethylasesmentioning

confidence: 99%

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

2021

View full text Add to dashboard Cite

show abstract

“…[4] Further validation of LSD1 for epigenetic drug discovery comes from its high expression levels in other cancer types including sarcoma, neuroblastoma, bladder, gastric and lung. [5,6] One approach to targeting LSD1 involves the repurposing of monoamine oxidase (MAO) inhibitors that disrupt the FAD cofactor common to both enzymes. [7,8] The approved antidepressant (�)-tranylcypromine (1, Figure 1) for example, is a substrate mimic that is oxidized to radical cation 2, followed by strain induced cyclopropyl ring opening to the reactive intermediate 3 which covalently modifies FAD.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Carboxamide‐Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

et al. 2021

View full text Add to dashboard Cite

In memory of the late Professor Maurizio Botta 1950-2019 for his generous friendship and his many outstanding scientific contributions to medicinal chemistry.Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent submicromolar IC 50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.

show abstract

“…[4] Further validation of LSD1 for epigenetic drug discovery comes from its high expression levels in other cancer types including sarcoma, neuroblastoma, bladder, gastric and lung. [5,6] One approach to targeting LSD1 involves the repurposing of monoamine oxidase (MAO) inhibitors that disrupt the FAD cofactor common to both enzymes. [7,8] The approved antidepressant (±)-tranylcypromine (1, Figure 1) for example, is a substrate mimic that is oxidized to radical cation 2, followed by strain induced cyclopropyl ring opening to the reactive intermediate 3 which covalently modifies FAD.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Carboxamides Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors for AML

Borrello

Tam²,

Shafat³

et al. 2021

Preprint

View full text Add to dashboard Cite

Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5a and 5b, had potent submicromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The t-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.

show abstract

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

Cited by 5 publications

References 187 publications

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

Lysine Demethylases: Promising Drug Targets in Melanoma and Other Cancers

Synthesis of Carboxamide‐Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

Synthesis of Carboxamides Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors for AML

Contact Info

Product

Resources

About