P4‐404: Ory‐2001: An Epigenetic Drug for the Treatment of Cognition Defects in Alzheimer’S Disease and Other Neurodegenerative Disorders

Maes, Tamara; Mascaró, Cristina; Rotllant, David; Cavalcanti, Fernando; Carceller, Elena; Ortega, Alberto; Molinero, César; Buesa, Carlos

doi:10.1016/j.jalz.2016.07.149

Cited by 7 publications

(10 citation statements)

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“…ORY-2001 is an orally active and blood-brain barrier (BBB)–permeable therapeutic agent that shows excellent selectivity to LSD1 and its homology MAO-B over chromatin modulators, other amine oxidases containing FAD, and 100 targets from the CEREP diversity panel. For Huntington’s disease, ORY-2001 is effective in preventing development of cognitive impairment in the R6/1 model and the SAMP-8 mice [88]. ORY-2001 restores behavioral deficits and UCHL1 (ubiquitin carboxyl-terminal esterase L1) and Notch1 levels in SAMP8 mice, a model for aging and AD [89].…”

Section: Lsd1/kdm1a Inhibitors In Clinical Trialsmentioning

confidence: 99%

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

2019

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Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.

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Section: Lsd1/kdm1a Inhibitors In Clinical Trialsmentioning

confidence: 99%

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

2019

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“…As far as various neurological disorders are concerned, epigenetic modifications have long been implicated in the nervous system’s aging, plasticity and memory ( Jakovcevski and Akbarian, 2012 ). ORY-2001 is the first Alzheimer’s related epigenetic drug that entered clinical phase I last year ( Maes et al, 2016 ; Meighan-Mantha, 2017 ). Huntington’s (HD) is another neurodegenerative disease caused by a polyglutamine repeat sequence in the huntingtin protein, which inhibits HATs leading to a decrease of H3 and H4 histone acetylation.…”

Section: Interventions and Future Aspectsmentioning

confidence: 99%

Epigenetics and Metabolism in Health and Disease

Tzika¹,

Dreker²,

Imhof

2018

Front. Genet.

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In the next 10 years, one billion people are estimated to suffer from disabling consequences of metabolic disorders, making them the number one noncommunicable disease on a global scale by 2030. Lots of risk factors such as dietary intake, lack of exercise and other life style behaviors are considered to play a role in the development of metabolic disorders. Despite the efforts that have been undertaken to unravel their potential causes, the underlying molecular mechanisms remain elusive. Evidence suggests that the pathogenesis involves changes on chromatin and chromatin-modifying enzymes, which can contribute to a persistent dysregulated metabolic phenotype. Indeed, a rising number of studies links epigenetic alterations with the diagnosis and prognosis of metabolic disorders. A prerequisite for exploiting these findings for pharmacological intervention is a detailed understanding of how differential epigenetic modifications control cell metabolism. In this mini review, we summarize the recent advances in uncovering the interplay between epigenetics and metabolic pathways on a cellular level and highlight potential new avenues for alternative treatment strategies.

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“…Treatment with 64 could downregulate the expression of inflammatory genes, including S100a9, and regulate the expression of genes correlated with neuroplasticity and behavior in the SAMP-8 mouse brain. An in vivo efficacy study demonstrated that 64 was able to reduce aggression and increase social behavior in SAMP-8 mice . This inhibitor was advanced into a phase IIa clinical trial in patients with mild to moderate Alzheimer’s disease in 2019 (NCT03867253).…”

Section: Targeting Epigenetic Erasers With Covalent Small-molecule In...mentioning

confidence: 99%

“…An in vivo efficacy study demonstrated that 64 was able to reduce aggression and increase social behavior in SAMP-8 mice. 156 This inhibitor was advanced into a phase IIa clinical trial in patients with mild to moderate Alzheimer's disease in 2019 (NCT03867253).…”

Section: Targeting Epigenetic Erasers Withmentioning

confidence: 99%

Targeting Epigenetic Regulators with Covalent Small-Molecule Inhibitors

Zhang

Rong

et al. 2021

J. Med. Chem.

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Epigenetic regulation of gene expression plays a critical role in various physiological processes, and epigenetic dysregulation is implicated in a number of diseases, prominently including cancer. Epigenetic regulators have been validated as potential therapeutic targets, and significant progress has been made in the discovery and development of epigenetic-based inhibitors. However, successful epigenetic drug discovery is still facing challenges, including moderate selectivity, limited efficacy, and acquired drug resistance. Inspired by the advantages of covalent small-molecule inhibitors, targeted covalent inhibition has attracted increasing interest in epigenetic drug discovery. In this review, we comprehensively summarize the structure-based design and characterization of covalent inhibitors targeting epigenetic writers, readers, and erasers and highlight their potential benefits in enhancing selectivity across the enzyme family and improving in vivo efficacy. We also discuss the challenges and opportunities of covalent small-molecule inhibitors and hope to shed light on future epigenetic drug discovery.

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P4‐404: Ory‐2001: An Epigenetic Drug for the Treatment of Cognition Defects in Alzheimer’S Disease and Other Neurodegenerative Disorders

Cited by 7 publications

References 0 publications

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

Epigenetics and Metabolism in Health and Disease

Targeting Epigenetic Regulators with Covalent Small-Molecule Inhibitors

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