Michael Schnekenburger

Natural Compound Histone Deacetylase Inhibitors (HDACi): Synergy with Inflammatory Signaling Pathway Modulators and Clin...

Published in Molecules

The remarkable complexity of cancer involving multiple mechanisms of action and specific organs led researchers Hanahan and Weinberg to distinguish biological capabilities acquired by cancer cells during the multistep development of human tumors to simplify its understanding. These characteristic hallmarks include the abilities to sustain prolifera...

4-Hydroxybenzoic acid derivatives as HDAC6-specific inhibitors modulating microtubular structure and HSP90α chaperone ac...

Published in Biochemical Pharmacology

Histone deacetylase (HDAC)6 is a unique isoenzyme targeting specific substrates including α-tubulin and heat shock protein (HSP)90. HDAC6 is involved in protein trafficking and degradation, cell shape and migration. Deregulation of HDAC6 activity is associated with a variety of diseases including cancer leading to a growing interest for developing ...

Perspectives in Medicinal Chemistry: DNA Methylation and Demethylation Mechanisms as Therapeutic Targets?

Published in Current Topics in Medicinal Chemistry

A majority of cancers display alterations in epigenetic mechanisms, such as aberrant DNA methylation at CpG islands (CGIs). This local hypermethy-lation of CGIs is associated with gene silencing leading to loss of tumor sup-pressor gene (TSG) functions that are critical for the control of tumor devel-opment. Concomitantly, global genomic hypomethyl...

Role of Histone Acetylation in Cell Cycle Regulation

Published in Current Topics in Medicinal Chemistry

Core histone acetylation is a key prerequisite for chromatin decondensation and plays a pivotal role in regulation of chromatin structure, function and dynamics. The addition of acetyl groups disturbs histone/DNA interactions in the nucleosome and alters histone/histone interactions in the same or adjacent nucleosomes. Acetyl groups can also provid...

Epigenetic alterations as a universal feature of cancer hallmarks and a promising target for personalized treatments

Published in Current Topics in Medicinal Chemistry

Despite considerable scientific progress, the burden of cancer in our society remains a major public health problem. Tumorigenesis is recognized as a complex and multistep process that involves the accumulation of successive transformational events with multi-factorial etiology. Nevertheless, such events result in the acquisition of key hallmark ch...

Editorial (Thematic Issue: Novel Pharmaceutical Approaches by Natural Compound-Derived Epigenetic Regulators: Epigenetic...

Published in Current Topics in Medicinal Chemistry

Dual Induction of Mitochondrial Apoptosis and Senescence in Chronic Myelogenous Leukemia by Myrtucommulone A

Published in Anti-Cancer Agents in Medicinal Chemistry

Despite recent advances in the treatment of chronic myelogenous leukemia (CML), the development of drug resistance and minimal residual disease remain major challenges for the treatment of CML patients, thus highlighting the need to develop innovative new approaches to improve therapeutic outcome. Myrtucommulone A (MCA) is a nonprenylated acylphlor...

Histone deacetylase 6 in health and disease

Published in Epigenomics

Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and specific physiological roles. Indeed, HDAC6 deacetylates various substrates including α-tubulin and HSP90α, and is involved in protein traffi...

Plant-derived epigenetic modulators for cancer treatment and prevention

Published in Biotechnology Advances

Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machin...

Novel inhibitors of human histone deacetylases: Design, synthesis and bioactivity of 3-alkenoylcoumarines

Published in Bioorganic & Medicinal Chemistry Letters

Histone deacetylases (HDACs) are well-established, promising targets for anticancer therapy due to their critical role in cancer development. Accordingly, an increasing number of HDAC inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a large panel of chemical structures was described including coumarin-con...

Regulation of epigenetic traits of the glutathione S-transferase P1 gene: from detoxification toward cancer prevention a...

Published in Frontiers in Pharmacology

Glutathione S-transferases (GSTs) are phase II drug detoxifying enzymes that play an essential role in the maintenance of cell integrity and protection against DNA damage by catalyzing the conjugation of glutathione to a wide variety of exo- and endogenous electrophilic substrates. Glutathione S-transferase P1 (GSTP1), the gene encoding the pi-clas...

5-aza-2′-deoxycytidine-mediated c-myc Down-regulation Triggers Telomere-dependent Senescence by Regulating Human Telomer...

Increased proliferation rates as well as resistance to apoptosis are considered major obstacles for the treatment of patients with chronic myelogenous leukemia (CML), thus highlighting the need for novel therapeutic approaches. Since senescence has been recognized as a physiological barrier against tumorigenesis, senescence-based therapy could repr...

Bis(4-hydroxy-2H-chromen-2-one): Synthesis and effects on leukemic cell lines proliferation and NF-κB regulation

Published in Bioorganic & Medicinal Chemistry

Synthesis of the bis-4-hydroxycoumarin-type compound, 3,3'-[3-(2-hydroxyphenyl)-3-oxopropane-1,1-diyl]bis(4-hydroxy-2H-chromen-2-one), was performed by two alternative pathways, either involving a basic organocatalyzed 1,4-conjugate addition tandem reaction of 4-hydroxycoumarin on chromone-3-carboxylic acid, or a double condensation of 4-hydroxycou...

Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA...

Published in PLoS ONE

Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the lu...

The Ah Receptor Recruits IKK  to Its Target Binding Motifs to Phosphorylate Serine-10 in Histone H3 Required for Transcr...

Published in Toxicological Sciences

Aryl hydrocarbon receptor (AHR) activation by xenobiotic ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is key to their toxicity. Following activation and nuclear translocation, AHR heterodimerizes with the AHR nuclear translocator (ARNT) and binds to AHR response elements (AhREs) in the enhancer of target genes, of which Cyp1a1 is the ...