ABSTRACT
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. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation S100A9 is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.
Subject(s)
Enzyme Inhibitors/pharmacology , Histone Demethylases/antagonists & inhibitors , Memory Disorders/drug therapy , Monoamine Oxidase Inhibitors/pharmacology , Oxadiazoles/pharmacology , Aging/drug effects , Aging/psychology , Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Animals , Behavior, Animal/drug effects , Brain/drug effects , Brain/physiopathology , Disease Models, Animal , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Epigenesis, Genetic/drug effects , Female , Gene Expression/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacokinetics , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
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. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.
Subject(s)
Cell Differentiation/drug effects , Histone Demethylases/drug effects , Leukemia, Myeloid, Acute/drug therapy , Animals , Apoptosis/drug effects , Cell Line, Tumor/metabolism , Disease Models, Animal , Histone Demethylases/antagonists & inhibitors , Histone Demethylases/genetics , Humans , Leukemia, Myeloid, Acute/genetics , Mice , Stem Cells/drug effects , Stem Cells/metabolismABSTRACT
The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.
Subject(s)
Biphenyl Compounds/chemistry , Crotonates/chemistry , Enzyme Inhibitors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Toluidines/chemistry , Animals , Arthritis, Experimental/drug therapy , Binding Sites , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/therapeutic use , Computer Simulation , Dihydroorotate Dehydrogenase , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Humans , Hydroxybutyrates , Nitriles , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Protein Structure, Tertiary , Rats , Structure-Activity RelationshipABSTRACT
BACKGROUND: The authors analyzed the retinoblastoma (Rb) tumor-suppressor pathway in meningeal hemangiopericytomas (MHPCs). METHODS: : Immunohistochemical detection of the Rb pathway proteins (Rb; E2F transcription factor 1 [E2F1]; cyclins D1, D3, and E; cyclin-dependent kinase 4 [CDK4]; and the CDK4 inhibitor p16/INKa) was followed by double immunofluorescence (DIF) staining and laser-scanning confocal microscopy (LSCM) in 11 MHPC specimens and from 4 specimens of recurrent disease from 1, 2, and 4 recurrences (total, 18 specimens). RESULTS: : All specimens displayed Rb pathway alterations, including low or negative Rb protein expression (17 specimens), high Rb protein expression (1 specimen), and loss of p16/INK4a expression (17 specimens). High levels of positive cell-cycle regulators were observed for E2F1 (10 specimens), cyclin E (7 specimens), CDK4 (5 specimens), cyclin D3 (1 specimen), and cyclin D1 (1 specimen). DIF and LSCM revealed no or very weak Rb and E2F1 colocalization, indicating that Rb does not act as a growth suppressor. High levels of human mouse double-minute 2 (HDM2) expression were observed in a previous study of these tumors, and they displayed colocalization with E2F1 and Rb in the current study, which supports the argument that HDM2 activates E2F1 and inactivates Rb. CONCLUSIONS: : The current findings demonstrated that loss of Rb and p16/INKa expression and high E2F1 expression indicate impairment of the Rb suppressor pathway. HDM2 colocalization with E2F1 and Rb also indicates that Rb suppressor pathway inactivation and transactivation of DNA synthesis genes may play pathogenic roles in MHPCs. High expression levels of cyclin E, cyclin D1, cyclin D3, and CDK4 were associated with Rb suppressor pathway neutralization.
