Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis.

Lysine specific demethylase 1 (LSD1; also known as KDM1A), is an epigenetic modulator that modifies the histone methylation status. KDM1A forms a part of protein complexes that regulate the expression of genes involved in the onset and progression of diseases such as cancer, central nervous system (CNS) disorders, viral infections, and others. Vafidemstat (ORY-2001) is a clinical stage inhibitor of KDM1A in development for the treatment of neurodegenerative and psychiatric diseases.

Comprehensive Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology.

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies.

First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat.

Background: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo.

Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.

Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription.

Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays.

The assessment of the target engagement, defined as the interaction of a drug with the protein it was designed for, is a basic requirement for the interpretation of the biological activity of any compound in drug development or in basic research projects. In epigenetics, target engagement is most often assessed by the analysis of proxy markers instead of measuring the union of the compound to the target. Downstream biological readouts that have been analyzed include the histone mark modulation or gene expression changes.

Chemoprobe-based assays of histone lysine demethylase 1A target occupation enable pharmacokinetics and pharmacodynamics studies of KDM1A inhibitors.

Screening of cellular activity for inhibitors of histone lysine modifiers is most frequently performed indirectly by analyzing changes in the total levels of histone marks targeted by lysine methylases/demethylases. However, inhibition of histone lysine modifiers often leads to local rather than total changes in histone marks. Also, because histone modifications can be modulated by more than one cellular enzyme, it is not always clear whether changes in histone marks are a direct or indirect consequence of the inhibitor treatment applied.

ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia.

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia.

KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease.

Histone methylation and demethylation are important processes associated with the regulation of gene transcription, and alterations in histone methylation status have been linked to a large number of human diseases. Initially thought to be an irreversible process, histone methylation is now known to be reversed by two families of proteins containing over 30 members that act to remove methyl groups from specific lysine residues present in the tails of histone H3 and histone H4. A rapidly growing number of reports have implicated the FAD-dependent lysine specific demethylase (KDM1) family in cancer, and several small-molecule inhibitors are in development for the treatment of cancer.

A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency.

Cellular processes requiring access to the DNA genome are regulated by an overlay of epigenetic modifications, including histone modification and chromatin remodeling. Similar to the cellular host, many nuclear DNA viruses that depend upon the host cell's transcriptional machinery are also subject to the regulatory impact of chromatin assembly and modification. Infection of cells with alphaherpesviruses (herpes simplex virus [HSV] and varicella-zoster virus [VZV]) results in the deposition of nucleosomes bearing repressive histone H3K9 methylation on the viral genome.

Specific Jak3 Downregulation in Lymphocytes Impairs γc Cytokine Signal Transduction and Alleviates Antigen-driven Inflammation In Vivo.

Jak3, one of the four members comprising the Jak family of cytosolic tyrosine kinases, has emerged as a promising target for nontoxic immunotherapies. Although a number of Jak inhibitors has already demonstrated efficacy, they suffer from secondary effects apparently associated to their pan-Jak activity. However, whether selective Jak3 inhibition would afford therapeutic efficacy remains unclear.

Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer.

HMGCS2, the gene that regulates ketone body production, is expressed in liver and several extrahepatic tissues, such as the colon. In CaCo-2 colonic epithelial cells, the expression of this gene increases with cell differentiation. Accordingly, immunohistochemistry with specific antibodies shows that HMGCS2 is expressed mainly in differentiated cells of human colonic epithelium.

Mouse neuron navigator 1, a novel microtubule-associated protein involved in neuronal migration.

The development of the nervous system (NS) requires the coordinated migration of multiple waves of neurons and subsequent processes of neurite maturation, both involving selective guidance mechanisms. In Caenorhabditis elegans, unc-53 codes for a new multidomain protein involved in the directional migration of a subset of cells. We describe here the first functional characterization of the mouse homologue, mouse Neuron navigator 1 (mNAV1), whose expression is largely restricted to the NS during development.