Phase I trials of the lysine-specific demethylase 1 inhibitor, GSK2879552, as mono- and combination-therapy in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes

Roboz, Gail J.; Yee, Karen; Verma, Amit; Borthakur, Gautam; Burguera, Adolfo de la Fuente; Sanz, Guillermo; Mohammad, Helai P.; Kruger, Ryan G.; Karpinich, Natalie O.; Ferron‐Brady, Geraldine; Acusta, Andre; Buono, Heather Del; Collingwood, Therese S.; Ballas, Marc; Dhar, Arindam; Wei, Andrew H.

doi:10.1080/10428194.2021.2012667

Cited by 15 publications

(4 citation statements)

References 10 publications

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“…The same research group has demonstrated that LSD1 expression in NHL is associated with chemoresistance [124], so the use of LSD1 inhibitors could be a new approach in drug-resistant lymphomas. In fact, LSD1 inhibitor GSK2879552 showed results in the phase I trial to relapsed/refractory myelodysplastic syndromes treatment [125]. Other LSD1 inhibitors are being tested.…”

Section: Demethylation and Deacetylation Drugs As Treatment For Canin...mentioning

confidence: 99%

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Montaner-Angoiti

Marín-García

Llobat

2023

Animals

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Canine malignant lymphoma is a common neoplasia in dogs, and some studies have used dogs as a research model for molecular mechanisms of lymphomas in humans. In two species, chemotherapy is the treatment of choice, but the resistance to conventional anticancer drugs is frequent. The knowledge of molecular mechanisms of development and progression of neoplasia has expanded in recent years, and the underlying epigenetic mechanisms are increasingly well known. These studies open up new ways of discovering therapeutic biomarkers. Histone deacetylases and demethylase inhibitors could be a future treatment for canine lymphoma, and the use of microRNAs as diagnosis and prognosis biomarkers is getting closer. This review summarises the epigenetic mechanisms underlying canine lymphoma and their possible application as treatment and biomarkers, both prognostic and diagnostic.

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Section: Demethylation and Deacetylation Drugs As Treatment For Canin...mentioning

confidence: 99%

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Montaner-Angoiti

Marín-García

Llobat

2023

Animals

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“…In 2019, Roiban's team reported a wild-type IRED IR46, which was designed to catalyze the biosynthesis of the lysinespecific demethylase 1 inhibitor GSK2879552. 50 After three rounds of directed evolution, the mutant of IR46-M3 showed optimal stability and catalytic activity. The research team used the evolved enzyme to produce the key intermediate of GSK2879552 in three batches of 20 L reaction, and 1.4 kg of amination product was obtained with 84% yield, 99.9% purity, and >99.7% ee.…”

Section: Ired-mediated Synthesis Of Representative Drugsmentioning

confidence: 99%

“…In 2019, Roiban’s team reported a wild-type IRED IR46, which was designed to catalyze the biosynthesis of the lysine-specific demethylase 1 inhibitor GSK2879552 . After three rounds of directed evolution, the mutant of IR46-M3 showed optimal stability and catalytic activity.…”

Section: Ired-mediated Synthesis Of Representative Drugsmentioning

confidence: 99%

Application of Imine Reductase in Bioactive Chiral Amine Synthesis

Wang,

Gao,

Gao

et al. 2024

Org. Process Res. Dev.

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Nitrogen-containing compounds, especially those with chiral amine structures, play a pivotal role in the field of organic active pharmaceutical ingredients. Traditional racemate resolution and chemical synthesis methods for the preparation of chiral amines suffer drawbacks such as high cost and environmental pollution. Over the past decades, stereoselective synthesis of nitrogen-containing compounds by biocatalytic methods such as imine reductase (IRED)-mediated transformation has become increasingly prominent. The prominence of imine reductases lies in their capacity to catalyze the reductive amination of aldehydes or ketones with primary or secondary amines, as well as their broader substrate scope. Furthermore, imine reductases exhibit diverse catalytic cycling systems that are unaffected by adverse reaction equilibria. This article focuses on the development of drug molecules or intermediates in biocatalytic synthesis mediated by imine reductase.

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“…To date, three phase I clinical trials for the evaluation of the safety, PK, and PD of GSK2879552 either alone or in combination with azacytidine for treating r/r SCLC (NCT02034123), r/r AML (NCT02177812) and high‐risk MDS (NCT02929498; EudraCT 2016‐002294‐35) have been terminated due to the unsatisfactory disease control outcomes and a notable incidence of adverse event (AE) rate among the patients 155–157 …”

Section: Inhibitors Of Lsd1 In Clinical Trialsmentioning

confidence: 99%

LSD1 in drug discovery: From biological function to clinical application

Liu,

Zhou,

Chen

et al. 2023

Medicinal Research Reviews

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Lysine‐specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono‐, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1‐targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

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Phase I trials of the lysine-specific demethylase 1 inhibitor, GSK2879552, as mono- and combination-therapy in relapsed/refractory acute myeloid leukemia or high-risk myelodysplastic syndromes

Cited by 15 publications

References 10 publications

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Application of Imine Reductase in Bioactive Chiral Amine Synthesis

LSD1 in drug discovery: From biological function to clinical application

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