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.
Highlights
KDM1A is a flavin adenine dinucleotide (FAD) dependent amine oxidase that acts primarily as a histone demethylase [1]
KDM1A is inhibited by covalent binding of ORY-2001 to the FAD cofactor, as shown by changes in the absorbance spectrum of the FAD cofactor and by MALDI-TOF Mass Spectrometry (S1B and S1C Fig)
Contrary to what happens in KDM1A-E8a KO mice, where the immediate early genes (IEGs) response is compromised; we have shown that chronic pharmacological modulation of KDM1A by ORY-2001 in Senescence Accelerated Mouse Prone 8 (SAMP8) mice facilitates the response of IEGs and shifts the epigenetic balance in a manner favorable to memory
Summary
KDM1A is a flavin adenine dinucleotide (FAD) dependent amine oxidase that acts primarily as a histone demethylase [1]. KDM1A is recruited by zinc finger (ZNF) TFs into repressive complexes, interacts tightly with RCOR and HDAC1/2 [2] and demethylates primarily H3K4me2/1 marks, associated with the active transcription state [3]. KDM1A was identified in protein complexes associated with activation of transcription, and in this context the protein was described to demethylate H3K9me2/1 [4] or H4K20me2 [5]. Certain types of leukemia and solid cancer types like small cell lung cancer are highly sensitive to both KDM1A knock-down and inhibition [6,7,8], and several selective KDM1A inhibitors are in Phase I and II clinical trials for the treatment of hematological or solid tumor indications
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