P2, N=4, Active, not recruiting, Terrence J Bradley, MD | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P1, N=18, Suspended, Terrence J Bradley, MD | Recruiting --> Suspended | Trial primary completion date: Nov 2024 --> Nov 2025

P1, N=52, Terminated, Taiho Oncology, Inc. | N=80 --> 52 | Trial completion date: Dec 2025 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Feb 2024; The study was terminated due to the changing treatment landscape, difficulty in enrolling eligible participants, and little likelihood of providing meaningful clinical benefit for the participants.

Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.

Notably, the most promising compound 23e showed a favorable oral PK profile and effectively suppressed the tumor growth in an AML xenograft model. Overall, our medicinal chemistry efforts provide compound 23e as a lead compound for developing LSD1 inhibitors for the treatment of AML and other advanced malignancies.

In this review, we outline the role of LSD1 in tumor immunity in terms of both innate and adaptive immunity, summarizing the mechanisms associated with LSD1-mediated tumor immunity and its potential regulatory capacity in tumor immune escape. Finally, we summarize the research status of LSD1 inhibitors in tumor immunotherapy, which be valuable for promoting the development of effective LSD1-targeted agents used as combination immunotherapy drugs.

Collectively, KDM1A promoted EOC cell proliferation, migration, and invasion, and reduced apoptosis by activating the ZFP64/CENPL axis, which triggered EOC progression. The online version contains supplementary material available at 10.1007/s10616-024-00671-w.

Mechanistically, LSD1 demethylates LC3B, leading to decreased LC3B stability. The observed inverse correlation between LSD1 expression and LC3B protein levels in clinical samples underscores the need for further investigation to elucidate how reduced LC3B protein levels induced by LSD1 demethylation may contribute to ovarian cancer.

P3, N=300, Recruiting, Merck Sharp & Dohme LLC | Trial primary completion date: May 2029 --> Apr 2027

Pulrodemstat is an effective therapeutic drug for HNSCC. Thus, the TET3/KDM1A axis may account for the malignant phenotype of HNSCC.

Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3. Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.

Compound 20c effectively modulated the expression of biomarkers associated with LSD1 and HDAC inhibition and demonstrated superior antiproliferative activity compared to SAHA and 4SC-202 across multiple colorectal cancer cell lines...It demonstrated significantly enhanced antitumor efficacy compared to SAHA, without causing observable toxicity. These findings highlight the potential of LSD1/HDAC dual inhibitors for the treatment of malignant cancers.

And miR-1270 inhibited ZO-1 expression in human endothelial cells, which enhanced their permeability. Our study uncovered a novel mechanism in which the LSD1 promotes the formation of pre-metastatic niches via the regulation of exosomal miRNA.

P3, N=300, Not yet recruiting, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Union Hospital, Tongji Medical College, Huazhong University of

Ipragliflozin was identified as a small-molecule inhibitor of ZNF480 and LSD1 interaction that may block breast cancer progression...Mechanistically, ZNF480 accelerates proliferation and neoadjuvant chemotherapy resistance in breast cancer cells via the AKT-GSK3β-Snail pathway by interacting with and stabilizing LSD1 in a competitive manner within TRIM28. This research has implications for developing targeted drugs against chemotherapy resistance in breast cancer.

The altered H3K4me2/H3K4me3 status induced by S2172 treatment affected the expression of genes related to tumorigenesis. Our data suggest that targeting LSD1 with S2172 could provide a promising treatment option for glioblastomas, particularly due to targeting of GSC populations.

Moreover, RBMS3/Twist1/MMP2, the downstream signaling pathway of LSD1, was activated after IFA treatment to inhibit the metastasis of MDA-MB-231 cells in vitro and in vivo. This study provided novel molecular templates for development of LSD1 covalence-binding inhibitor and laid a foundation for developing agents against breast carcinoma metastasis for targeting LSD1.

P1, N=45, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Oct 2024 --> Jul 2025

Our findings highlight JMJD1B's role in maintaining genome integrity by ensuring a proper histone supply to the nucleus, expanding its function beyond gene expression regulation. JMJD1B emerges as a crucial player in preserving genome stability and the development of melanoma, with a potential role as a safeguard against oncogenic mutations.

Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

P1, N=16, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

In conclusion, our study provides compelling evidence that apigenin inhibits liver cancer progression and elucidates its mechanism of action in regulating lipid metabolism. Specifically, we find that apigenin suppresses the progression of HCC cells by downregulating genes involved in lipid metabolism. Additionally, our results indicate that KDM1A acts as a downstream target of apigenin in the inhibition of lipid metabolism in HCC. These findings offer experimental support for the potential use of apigenin as a therapeutic agent for liver cancer, highlighting its relevance in future clinical applications.

P1/2, N=3, Terminated, University of Washington | Trial completion date: Jan 2026 --> Apr 2024 | Active, not recruiting --> Terminated; Closed per SRC Low Accrual Policy

In conclusion, YY1 upregulation increased KDM1A expression via transcriptional activation. USP1 stabilized KDM1A through deubiquitination to promote TNBC progression.

Herein, in this review, we summarized the mechanisms how LSD1 regulates cell stemness comprehensively. In addition, some related inhibitors targeting LSD1 to reduce the proliferation characteristics of cancer stem cells are also described.

P1, N=16, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=81, Completed, Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) | Active, not recruiting --> Completed

ORY-1001 down-regulates the Notch/HES1 pathway by inhibiting LSD1 expression to suppress the growth of GBM in mice.

In vivo, Z-1 exhibited significant suppression effect on the growth of gastric cancer cells without obvious toxicity. Therefore, Z-1 represents a potential novel immunomodulator that targets LSD1, providing a lead compound with new function mechanism for gastric cancer treatment.

By analyzing the database of miR-1290 target gene NAT1, we verified that miR-1290 could regulate the expression of NAT1. These data provide fresh insights into the biology of breast cancer therapy by demonstrating how the epigenetic factor LSD1 stimulates the breast cancer cells' invasion and migration via controlling exosomal miRNA.

Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.

In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.

P1, N=90, Completed, Celgene | Active, not recruiting --> Completed

We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.

Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.

Additionally, AG490 injection effectively reduced HIF-1α and VEGFA expression in the CNV model. These findings suggest that LSD1 inhibition via the HIF-1α-driven pathway prevents angiogenesis, oxidative stress, and ferroptosis in corneal alkali burn-induced CNV, highlighting LSD1 as a potential therapeutic target.

These new insights allow us to propose the KDM1A genetic screening to all PBMAH patients with signs of FDCS (low fasting cortisol that increases after a mixed meal or oral glucose load) and to all first-degree relatives of KDM1A variant carriers. Given that KDM1A is a tumor suppressor gene that has also been associated with monoclonal gammopathy of uncertain significance and multiple myeloma, the investigation of FDCS in the diagnostic management of patients with PBMAH and further genetic testing and screening for malignancies should be encouraged.

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

P1, N=9, Not yet recruiting, Medical College of Wisconsin

P1, N=50, Recruiting, Oryzon Genomics S.A. | Trial completion date: Jun 2026 --> Nov 2025

Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient-derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis...Importantly, KDM1A-KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

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