<scp>LSD</scp>1 (<scp>KDM</scp>1A)‐independent effects of the <scp>LSD</scp>1 inhibitor <scp>SP</scp>2509 in cancer cells

Sonnemann, Jürgen; Zimmermann, Miriam; Marx, Christian; Ebert, Franziska; Becker, Sabine; Lauterjung, Marie-Luise; Beck, James F.

doi:10.1111/bjh.14983

Cited by 21 publications

(20 citation statements)

References 9 publications

(10 reference statements)

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“…Similarly, this could also explain the previously observed reversal of the EWS‐FL1 signature effects with SP2509 in Ewing sarcoma cells . However, it is noteworthy that SP2509 has been shown to effectively cause cell death regardless of KDM1A expression in a leukemia KDM1A knockout cell line and its isogenic control . In addition to disrupting KDM1A's complex formation capabilities, SP2509 may have additional cytotoxic effects independent from KDM1A binding.…”

Section: Discussionmentioning

confidence: 52%

“…10 However, it is noteworthy that SP2509 has been shown to effectively cause cell death regardless of KDM1A expression in a leukemia KDM1A knockout cell line and its isogenic control. 41 In addition to disrupting KDM1A's complex formation capabilities, SP2509 may have additional cytotoxic effects independent from KDM1A binding. Consistent with this, 2-hydroxyphenyl-hydrazone structural motif within SP2509 has previously been identified as a pan-assay interference flag and has the potential to elicit promiscuous biological activity.…”

Section: Global or Promoter-specific Accumulation Of Methylation Of H3k4mentioning

confidence: 99%

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Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Romo-Morales

Aładowicz

Blagg

et al. 2019

Pediatric Blood & Cancer

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Background Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are rare and clinically aggressive sarcomas usually characterized by oncogenic fusion proteins involving EWS. Emerging studies of Ewing sarcoma have demonstrated EWS‐FLI1‐driven chromatin remodeling as a key aspect of tumorigenicity. In particular, the lysine‐specific demethylase KDM1A/LSD1 is linked to transcriptional regulation of target genes orchestrated by the EWS portion of the fusion protein interacting with repressive chromatin‐remodeling complexes. Consistent with this model, depletion of KDM1A supports it is a molecular therapeutic target in Ewing sarcoma cells, but effective drugs need to be identified. Procedure A comprehensive phenotypic analysis of the effects of catalytic KDM1A inhibitors ORY‐1001 and GSK2879552, including clinically relevant doses, was carried out in 2D and 3D spheroid models of Ewing sarcoma and DSRCT. Results Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays and had no impact on invasion in a 3D assay. Conclusions Overall, evidence presented here does not support inhibition of KDM1A catalytic demethylase activity as an effective therapeutic strategy for Ewing sarcoma or DSRCT. However, roles of KDM1A beyond its demethylase activity should be considered for these sarcomas.

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Section: Discussionmentioning

confidence: 52%

Section: Global or Promoter-specific Accumulation Of Methylation Of H3k4mentioning

confidence: 99%

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Romo-Morales

Aładowicz

Blagg

et al. 2019

Pediatric Blood & Cancer

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“…Furthermore, the findings of Sonnemann et al . () demonstrate a decrease in cell viability in LSD1 knockout cells upon HCI‐2509 treatment, suggesting potential off‐targets of HCI‐2509 that as yet remain unidentified. Nevertheless, in their initial study, Sorna et al .…”

Section: Discussionmentioning

confidence: 96%

“…HCI-2508 is a derivative of the 4-hydroxy-phenyl-hydrazone core structure that has previously been identified to cause several off-target hits in several drugs (Baell and Holloway, 2010). Furthermore, the findings of Sonnemann et al (2017) demonstrate a decrease in cell viability in LSD1 knockout cells upon HCI-2509 treatment, suggesting potential off-targets of HCI-2509 that as yet remain unidentified. Nevertheless, in their initial study, Sorna et al (2013) demonstrated the high selectivity of HCI-2509 towards LSD1.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

et al. 2018

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Lung adenocarcinoma (LUAD) is the most prevalent subtype of non‐small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5‐year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine‐specific demethylase 1 (LSD1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD. Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD1 as a novel therapeutic option for treating LUAD. The reversible LSD1 inhibitor HCI‐2509 significantly reduced cell growth with an IC 50 of 0.3–5 μm in vitro, which was linked to an enhancement of histone 3 lysine methylation. Most importantly, growth arrest, as well as inhibition of the invasion capacities, was independent of the underlying driver mutations. Subsequent expression profiling revealed that the cell cycle and replication machinery were prominently affected after LSD1 inhibition. In addition, our data provide evidence that LSD1 blockade significantly interferes with EGFR downstream signaling. Finally, our in vitro results were confirmed by preclinical therapeutic approaches, including the use of two autochthonous transgenic LUAD mouse models driven by either EGFR or KRAS mutations. Importantly, LSD1 inhibition resulted in significantly lower tumor formation and a strong reduction in tumor progression, which were independent of the underlying mutational background of the mouse models. Hence, our findings provide substantial evidence indicating that tumor growth of LUAD can be markedly decreased by HCI‐2509 treatment, suggesting its use as a single agent maintenance therapy or combined therapeutical application in novel concerted drug approaches.

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Epigenetic compounds targeting pharmacological target lysine specific demethylase 1 and its impact on immunotherapy, chemotherapy and radiotherapy for treatment of tumor recurrence and resistance

Agboyibor

Dong

Effah

et al. 2023

Biomedicine & Pharmacotherapy

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LSD1 (KDM1A)‐independent effects of the LSD1 inhibitor SP2509 in cancer cells

Abstract: Additional Supporting Information may be found in the online version of this article: Fig S1. Effects of LSD1 inhibitors in Ewing's sarcoma cells. Fig S2. LSD1 expression in HAP1 and HAP1-LSD1-cells. Fig S3. Effects of SP2509 from different suppliers.

Cited by 21 publications

References 9 publications

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

Epigenetic compounds targeting pharmacological target lysine specific demethylase 1 and its impact on immunotherapy, chemotherapy and radiotherapy for treatment of tumor recurrence and resistance

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