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.

We present the crystalline organization of 33 all-AT deoxyoligonucleotide duplexes, studied by x-ray diffraction. Most of them have very similar structures, with Watson-Crick basepairs and a standard average twist close to 36 degrees. The molecules are organized as parallel columns of stacked duplexes in a helical arrangement. Such organization of duplexes is very regular and repetitive: all sequences show the same pattern. It is mainly determined by the stacking of the terminal basepairs, so that the twist in the virtual TA base step between neighbor duplexes is always negative, approximately -22 degrees. The distance between the axes of parallel columns is practically identical in all cases, approximately 26 A. Interestingly, it coincides with that found in DNA viruses and fibers in their hexagonal phase. It appears to be a characteristic distance for ordered parallel DNA molecules. This feature is due to the absence of short range intermolecular forces, which are usually due to the presence of CG basepairs at the end of the oligonucleotide sequence. The duplexes apparently interact only through their diffuse ionic atmospheres. The results obtained can thus be considered as intermediate between liquid crystals, fibers, and standard crystal structures. They provide new information on medium range DNA-DNA interactions.

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.