Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors.
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ABSTRACT:
SUBMITTER: Gehling VS
PROVIDER: S-EPMC7294731 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We have previously described the synthesis and evaluation of 3,5-diamino-1,2,4-triazole analogues as inhibitors of the flavin-dependent histone demethylase LSD1. These compounds are potent inhibitors of LSD1 without activity against monoamine oxidases A and B, and promote the elevation of H3K4me2 levels in tumor cells in vitro. We now report that the cytotoxicity of these analogues in pancreatic tumor cells correlates with the overexpression of LSD1 in each tumor type. In addition, we show that a subset of these 3,5-diamino-1,2,4-triazole analogues inhibit a related flavin-dependent oxidase, the polyamine catabolic enzyme spermine oxidase (SMOX) in vitro.
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Project description:Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1-P4 substrate recognition sequence of the enzyme. Preliminary structure-activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.
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Project description:Compounds that inhibit the catalytic function of lysine-specific demethylase 1 (LSD1) are interesting as therapeutic agents. Recently, we identified three lysine-phenylcyclopropylamine conjugates, NCD18, NCD25, and NCD41, which are potent LSD1 inactivators. However, in our previous study, because we tested those compounds as mixtures of (1S,2R)- and (1R,2S)-disubstituted cyclopropane rings, the relationship between the stereochemistry of the cyclopropane ring and their biological activity remained unknown. In this work, we synthesized optically active compounds of NCD18, NCD25, and NCD41 and evaluated their LSD1 inhibitory activities. In enzyme assays, the LSD1 inhibitory activities of (1R,2S)-NCD18 and (1R,2S)-NCD25 were approximately eleven and four times more potent than those of the corresponding (1S,2R)-isomers, respectively. On the other hand, (1S,2R)-NCD41 was four times more potent than (1R,2S)-NCD41. Binding simulation with LSD1 indicated that the aromatic rings of the compounds and the amino group of the cyclopropylamine were important for the interaction with LSD1, and that the stereochemistry of the 1,2-disubstituted cyclopropane ring affected the position of the aromatic rings and the hydrogen bond formation of the amino group in the LSD1 catalytic site. These findings are expected to contribute to the further development of LSD1 inactivators.
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Project description:Modulation of histone modifications in the brain may represent a new mechanism for brain disorder therapy. Post-translational modifications of histones regulate gene expression, affecting major cellular processes such as proliferation, differentiation, and function. An important enzyme involved in one of these histone modifications is lysine specific demethylase 1 (LSD1). This enzyme is flavin-dependent and exhibits homology to amine oxidases. Parnate (2-phenylcyclopropylamine (2-PCPA); tranylcypromine) is a potent inhibitor of monoamine oxidases and derivatives of 2-PCPA have been used for development of selective LSD1 inhibitors based on the ability to form covalent adducts with flavin adenine dinucleotide (FAD). Here we report the synthesis and in vitro characterization of LSD1 inhibitors that bond covalently to FAD. The two most potent and selective inhibitors were used to demonstrate brain penetration when administered systemically to rodents. First, radiosynthesis of a positron-emitting analog was used to obtain preliminary bio-distribution data and whole brain time-activity curves. Second, we demonstrate that this series of LSD1 inhibitors is capable of producing a cognitive effect in a mouse model. By using a memory formation paradigm, novel object recognition, we show that LSD1 inhibition can abolish long-term memory formation without affecting short-term memory, providing further evidence for the importance of reversible histone methylation in the function of the nervous system.
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Project description:Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.
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