P2, N=19, Completed, 4SC AG | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

Interestingly, specific Lsd1-interacting long non-coding RNAs (LINRs) were found to antagonize Bre1-mediated Lsd1 protein degradation. The intricate interplay discovered among the Lsd1 complex, LINRs and Bre1 provides insight into how Lsd1 protein stability is fine-tuned to underlie progenitor differentiation in vivo.

P1, N=90, Active, not recruiting, Celgene | Phase classification: P1b --> P1 | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Feb 2024 --> Jun 2024

CREB3 overexpression contributed to Donafenib resistance in HCC cells by activating the ZFAS1/p65 axis.

P1, N=20, Completed, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc. | Recruiting --> Completed

P1, N=75, Terminated, Celgene | Trial completion date: Sep 2025 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2025 --> Mar 2024; Business objectives have changed

This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively...Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.

Tan IIA promoted ferroptosis and inhibited tumor growth and metastasis via suppressing KDM1A/PIAS4/SLC7A11 axis.

P1/2, N=34, Suspended, University of Washington | Recruiting --> Suspended

P1, N=24, Not yet recruiting, OHSU Knight Cancer Institute

P3, N=400, Not yet recruiting, Merck Sharp & Dohme LLC

We further demonstrated that SP-2509 and OG-L002 disturbed fatty acid metabolism and induced lipid droplet accumulation through the impairment of lipophagy, but not bulk autophagy. These findings indicate a significant potential association of lipophagy and anticancer effects in glycolysis-suppressed PDAC cells, offering ideas for new therapeutic strategies for PDAC by dual inhibition of glycolysis and fatty acids metabolism.

Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage...Moreover, some post-transcriptional modifications and cellular metabolites can also regulate LSD1 expression or its demethylase activity. Therefore, in this review, we will systematically summarize how proteins involved in the transcriptional corepressor complex, various post-translational modifications, and metabolites act as regulatory factors for LSD1 activity.

P1, N=80, Active, not recruiting, Astex Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

P2, N=20, Active, not recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2025 --> Jan 2025

Pulrodemstat synergized with Lenvatinib based on suppression of PI3K-AKT signaling and activation of apoptotic signaling.

Here, we set out to identify an epigenetic regulator drug that acts synergistically with doxorubicin in EBV-positive lymphoma...We further observed that SOX2 expression was altered in response to CHAC2 expression, suggesting that stemness is regulated. Collectively, these findings suggest that LSD1 inhibitors could serve as promising therapeutic candidates for EBV-positive lymphoma, potentially reducing stemness activity when combined with conventional drugs to offer an effective treatment approach.

P2, N=42, Recruiting, Fox Chase Cancer Center | Trial primary completion date: Aug 2024 --> Aug 2025

P2, N=80, Active, not recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2024 --> Aug 2024

Importantly, the formation of TERRA-LSD1 condensates enriches the R-loop stimulating protein Rad51AP1 and increases TERRA-containing R-loops at telomeres. Our findings suggest that LSD1-TERRA phase separation enhances the function of R-loop regulatory molecules for ALT telomere maintenance, providing a mechanism for how the biophysical properties of histone modification enzyme-RNA interactions impact chromatin function.

In colorectal liver metastasis (CLM), TAM morphology correlates with prognosis, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger TAMs (L-TAMs)...The inflammatory stimuli promoted by TNFα induced the increased expression of riboflavin transporter SLC52A3 and LSD1 in M2 macrophages. The modulation of the riboflavin-LSD1 axis represents a potential target for reprogramming TAM subtypes, paving the way for promising anti-tumor therapeutic strategies.

LSD1 deficiency reduced hnRNPA2B1 expression in breast cancer cells by decreasing the level of H3K9me2 demethylation in the promoter region of the hnRNPA2B1 gene. Our study revealed that LSD1 plays a crucial role in the regulation of exosomal sorting of miRNA.

P1/2, N=45, Not yet recruiting, National Cancer Institute (NCI)

Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.

P2, N=92, Completed, Celgene | Active, not recruiting --> Completed

P1, N=50, Recruiting, Oryzon Genomics S.A. | Trial primary completion date: Jan 2024 --> Jan 2025

This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.

CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.

This result suggests that the hydrophobic interaction between the inhibitor peptides and LSD1 affects the LSD1-inhibitory activity. We believe that this SAR information provides a basis for the development of more potent LSD1 inhibitors.

In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.

An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6Tim-3 Tex cells in tumors and the expression level of Tcf1 in Id2-deleted CD8 T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8 T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

The xenograft assays also showed that DUSP4 overexpression-promoted ESCC tumor growth in vivo and LC3II and LSD1 protein expression in tumor tissues were reversed by rapamycin or anisomycin. Overall, DUSP4 inhibits Bcl2-Beclin1-autophagy signal transduction through the negative regulation of JNK, thus suppressing autophagic death and the autophagic degradation of LSD1 in ESCC, by which DUSP4 promotes ESCC carcinogenesis.

The results of this experiment demonstrated that the treatment of breast cancer cells with tamoxifen reduces the expression of VEGF and KDM1A by increasing miR-329. The treatment therefore reduces angiogenesis, and thus its anti-tumor effects are applied.

P2, N=20, Recruiting, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Trial completion date: Aug 2025 --> Apr 2025 | Trial primary completion date: Aug 2025 --> Apr 2025

P1/2, N=90, Completed, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Phase classification: P2 --> P1/2

P3, N=300, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

In contrast, the IC values obtained for the control (tranylcypromine) in exposure to MCF-7 and MDA-MB-231 cells were 104.6 ± 1.69 μM and 77 ± 0.67 μM, respectively. Arformoterol enhanced apoptosis and induced cell cycle arrest at the G2/M phase, both in MCF-7 and MDA-MB-231 cancer cells. Based on our findings, we propose that Arformoterol represents a promising candidate for breast cancer treatment, owing to its potent LSD1 inhibitory activity.

P1, N=50, Active, not recruiting, Salarius Pharmaceuticals, LLC

P1/2, N=44, Active, not recruiting, The Netherlands Cancer Institute

P1, N=91, Active, not recruiting, Celgene | Trial primary completion date: Aug 2023 --> Sep 2025