Comprehensive <i>in Vitro</i> Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

Sacilotto, Natalia; Dessanti, Paola; Lufino, Michele M. P.; Ortega, Alberto; Rodríguez-Gimeno, Alejandra; Salas, Jordi; Maes, Tamara; Buesa, Carlos; Mascaró, Cristina; Soliva, Robert

doi:10.1021/acsptsci.1c00223

Cited by 23 publications

(18 citation statements)

References 86 publications

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“…A recently published paper using separate GSC lines and a single LSD1 inhibitor DDP 38003, corroborates these findings and shows tumor regrowth with LSD1 knockdown, supporting a need to understand this process ( 37 ). Recently, a direct comparison of pharmacological inhibitors of LSD1 was described in AML and small cell lung cancer models ( 38 ), however, our study is the first to extend this comparison into clinically relevant patient-derived MDA-GSC lines. Using the MDA-GSC20 line, a radioresistant GBM model, in an orthotopic xenograft mouse model, a strong effect was observed after 7 weeks of treatment with GSK-LSD1.…”

Section: Discussionmentioning

confidence: 99%

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles

et al. 2023

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IntroductionImproved therapies for glioblastoma (GBM) are desperately needed and require preclinical evaluation in models that capture tumor heterogeneity and intrinsic resistance seen in patients. Epigenetic alterations have been well documented in GBM and lysine-specific demethylase 1 (LSD1/KDM1A) is amongst the chromatin modifiers implicated in stem cell maintenance, growth and differentiation. Pharmacological inhibition of LSD1 is clinically relevant, with numerous compounds in various phases of preclinical and clinical development, but an evaluation and comparison of LSD1 inhibitors in patient-derived GBM models is lacking.MethodsTo assess concordance between knockdown of LSD1 and inhibition of LSD1 using a prototype inhibitor in GBM, we performed RNA-seq to identify genes and biological processes associated with inhibition. Efficacy of various LSD1 inhibitors was assessed in nine patient-derived glioblastoma stem cell (GSC) lines and an orthotopic xenograft mouse model.ResultsLSD1 inhibitors had cytotoxic and selective effects regardless of GSC radiosensitivity or molecular subtype. In vivo, LSD1 inhibition via GSK-LSD1 led to a delayed reduction in tumor burden; however, tumor regrowth occurred. Comparison of GBM lines by RNA-seq was used to identify genes that may predict resistance to LSD1 inhibitors. We identified five genes that correlate with resistance to LSD1 inhibition in treatment resistant GSCs, in GSK-LSD1 treated mice, and in GBM patients with low LSD1 expression.ConclusionCollectively, the growth inhibitory effects of LSD1 inhibition across a panel of GSC models and identification of genes that may predict resistance has potential to guide future combination therapies.

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Section: Discussionmentioning

confidence: 99%

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles

et al. 2023

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“… 1 Half-maximal inhibition concentration (IC 50 ) using horseradish peroxidase–coupled assay. 2 Assayed under the same experimental conditions [ 50 ]. …”

Section: Inhibitors Of Fad–containing Lysine Demethylasesmentioning

confidence: 99%

Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

2023

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The dynamic regulation of histone methylation and demethylation plays an important role in the regulation of gene expression. Aberrant expression of histone lysine demethylases has been implicated in various diseases including intractable cancers, and thus lysine demethylases serve as promising therapeutic targets. Recent studies in epigenomics and chemical biology have led to the development of a series of small-molecule demethylase inhibitors that are potent, specific, and have in vivo efficacy. In this review, we highlight emerging small-molecule inhibitors targeting the histone lysine demethylases and their progress toward drug discovery.

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“…This calls into question the validity of seclidemstat as a reversible inhibitor of LSD1 (Figure ). ,, …”

Section: Lsd1 Inhibitorsmentioning

confidence: 99%

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

Baby,

Shinde,

Kulkarni

et al. 2023

ACS Chem. Biol.

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Aberrant expression of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been associated with the incidence of many diseases, particularly cancer, and it has evolved as a promising epigenetic target over the years for treatment. The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat). There is parallel mining for peptide-based LSD1 inhibitors, which exploits the opportunities in the LSD1 substrate binding pocket. This Review highlights the research progress on reversible and irreversible peptide/peptidederived LSD1 inhibitors. For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

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Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

Cited by 23 publications

References 86 publications

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles

Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics

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