SP-2509 / Salarius - LARVOL DELTA

N'‑(1-Phenylethylidene)benzohydrazide Cytotoxicity Is Lysine-Specific Demethylase 1 Independent and Linked to Iron-Sulfur Cluster Disruption in Ewing Sarcoma. (PubMed, ACS Pharmacol Transl Sci) - "The noncompetitive lysine-specific demethylase 1 (LSD1) inhibitors SP-2509 and SP-2577 are N'-(1-phenylethylidene)-benzohydrazides that display potent activity in Ewing sarcoma. This unique activity is instead associated with the N'-(2-hydroxybenzylidene)-benzohydrazide core and destabilization of Fe-S proteins. These findings reveal a novel mechanism of action for this class of compounds and raise additional questions regarding how EWSR1::FLI1 transcriptional regulation is linked to Fe-S biogenesis, the precise mechanisms of cell death, the biological features of susceptible cancer cells, and strategies for clinical translation."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • EWSR1 • FLI1

Seclidemstat (SP-2577) induces transcriptomic reprogramming and cytotoxicity in multiple fusion-positive sarcomas. (PubMed, Cancer Res Commun) - P1 | "Treatment with the small molecule SP-2509 results in reversal of the transcriptional activity of the FET fusion that causes Ewing sarcoma, EWSR1::FLI1. This included reversal of FET-fusion transcriptional signatures for EWSR1::WT1, EWSR1::ATF1, and EWSR1::ERG. Though novel inhibitors are unlikely to display single-agent efficacy in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged and other fusion positive sarcomas."

Journal • Ewing Sarcoma • Liposarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • ATF1 • EWSR1 • FLI1 • FUS • TAF15 • WT1

Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer. (PubMed, Biochem Biophys Res Commun) - "Our previous study demonstrated that the LSD1 inhibitor SP-2509 disrupts lipophagy independently of LSD1 inhibition, leading to LD accumulation and ATP depletion in glycolysis-suppressed PDAC cells...In PDAC, aberrant PDM formation under lipid stress may represent a maladaptive response contributing to metabolic vulnerability. This newly identified dysregulation of lipid and mitochondrial homeostasis may offer a new therapeutic target in treatment-resistant pancreatic cancer."

Journal • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

The oncogenic potentials of SUV39H2 and LSD1 in ovarian cancer (BGCS 2025) - " Representative ovarian cancer cell line models were established including BRCA-proficient, BRCA-null and cisplatin-resistant cells...The inhibition of LSD1 by SP2509 reduced cell viability in SKOV3, UWB1.289, OVCAR3, SKOV3-CisR and OVCAR3-CisR with IC50 of 0.8724 μM, 1.604 μM, 0.6828 μM, 2.033 μM and 7.265 μM, respectively at 72 hours... SUV39H2 regulates LSD1 in ovarian cancer. SUV39H2 and LSD1 could represent promising novel targets in ovarian cancer."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRCA • CDH1 • KDM1A

N'-(1-phenylethylidene)-benzohydrazide cytotoxicity is LSD1 independent and linked to Fe-S cluster disruption in Ewing sarcoma. (PubMed, bioRxiv) - "The noncompetitive LSD1 inhibitors SP-2509 and SP-2577 are N'-(1-phenylethylidene)-benzohydrazides that display potent activity in Ewing sarcoma. This unique activity is instead associated with the N'-(2-hydroxybenzylidene)-hydrazide core and destabilization of Fe-S proteins. These findings reveal a novel mechanism of action for this class of compounds and raise additional questions regarding how EWSR1::FLI1 transcriptional regulation is linked to Fe-S biogenesis, the precise mechanisms of cell death, the biological features of susceptible cancer cells, and strategies for clinical translation."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • EWSR1 • FLI1

Unveiling New Binding Sites and Allosteric Regulation Mechanisms of LSD1 for Novel Therapeutics. (PubMed, J Med Chem) - "SP2509, an allosteric LSD1 inhibitor, can affect both demethylase-dependent and -independent functions of LSD1...This unique binding mode is also validated through in vitro biochemical characterizations. These findings provide invaluable structural insights for designing next-generation LSD1 inhibitors for novel therapeutics."

Journal

Dual epigenetic targeting of hepatocellular carcinoma (AACR 2025) - "Patients with high expression levels of both EZH2 and LSD1 exhibit the poorest survival, suggesting that dual inhibition of these enzymes may offer a more effective therapeutic strategy than monotherapy in HCC.Dual inhibition of EZH2 and LSD1 using GSK126 (an EZH2 inhibitor) and SP2509 (an LSD1 inhibitor) more effectively suppresses liver cancer cell proliferation compared to single-agent treatments. Although EZH2 and LSD1 inhibitors are currently undergoing clinical trials for various cancers, their combination has not yet been explored in HCC. Therefore, evaluating this dual epigenetic therapy for HCC treatment represents a promising direction for future research with immediate translational potential."

Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CCND1 • EZH2 • KDM1A • PCNA

Lysine-specific demethylase 1 controls key OSCC preneoplasia inducer STAT3 through CDK7 phosphorylation during oncogenic progression and immunosuppression. (PubMed, Int J Oral Sci) - "LSD1 inhibition by SP2509 disrupted cell cycle, reduced immunosuppression, and enhanced CD4+ and CD8+ T-cell infiltration. In a feline model of spontaneous OSCC, a clinical LSD1 inhibitor (Seclidemstat or SP2577) was found to be safe and effectively inhibit the STAT3 network...Notably, LSD1 inhibition reduced the phosphorylation of CDK7 at Tyr170 and eIF4B at Ser422, offering insights into a novel mechanism by which LSD1 regulates the preneoplastic-to-OSCC transition. This study provides a deeper understanding of OSCC progression and highlights LSD1 as a potential therapeutic target for controlling OSCC progression from preneoplastic lesions."

IO biomarker • Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • CD8 • CDK7 • CTLA4 • STAT3

Lysine-specific Demethylase 1A (LSD1) inhibition attenuates phenotypic transition and delays the tumor relapse to radioimmunotherapy in small cell lung cancer (ELCC 2025) - "Additionally, we evaluated the anti-tumor efficacy of the triple therapy of RT + ICI + LSD1 inhibitor (SP2509) in SCLC. Dynamic single-cell RNA-Seq data revealed that LSD1 expression was elevated in relapsed SCLC tumor cells, suggesting that these cells may exhibit lower sensitivity to RT + ICI treatment and contribute to tumor relapse following radioimmunotherapy... In our murine SCLC model, Lsd1+ tumor cells were found to be associated with relapse following RT + ICI treatment. Inhibition or knockout of LSD1 suppressed NeuroD1 and neuroendocrine transcriptional programs, increased T-cell infiltration, and delayed tumor relapse to radioimmunotherapy."

IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • KDM1A • NEUROD1

Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer. (PubMed, Cell Death Dis) - "SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis."

Journal • Lung Cancer • Metabolic Disorders • Oncology • Solid Tumor • MAP1LC3B • MEN1 • SQSTM1 • TFE3

A TBX2-driven signaling switch from androgen receptor to glucocorticoid receptor confers therapeutic resistance in prostate cancer. (PubMed, Oncogene) - "Notably, we report that SP2509, an allosteric inhibitor of the demethylase-independent function of LSD1 (a TBX2-interacting protein in the COREST complex) disrupts both TBX2-LSD1 and TBX2-GR protein-protein interactions, revealing a unique mode of SP2509 action in CRPC. Taken together, our study identifies the TBX2-driven AR- to GR- signaling switch as a molecular mechanism underlying enzalutamide resistance and provides key insights into a potential therapeutic approach for targeting this switch by disrupting TBX2-GR and TBX2-LSD1 protein-protein interactions."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • TBX2

LSD1 INHIBITOR SP-2509 DISRUPTS IRON-SULFUR CLUSTER BIOGENESIS (CTOS 2024) - "Inhibition of LSD1, by CRISPRi or OG-L002 shows no impact on cell viability over 72 hours. Changes in gene regulation and cell viability caused by SP-2509 appears independent of LSD1 inhibition. Our data indicate that SP-2509 and similar compounds disrupt the incorporation of Fe-S clusters into nascent Fe-S proteins."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • EWSR1 • FLI1 • LYRM7 • NDUFS1

Tumor Organoid predicted therapeutic responses to novel epigenetic drugs via high-throughput screening (SNO 2024) - "7 compounds (JIB-04, SP2509, AS-8351, GSK J4 HCI, 3-Deazaneplanocin A HCL, Chaetocin, TC-E-5003) were shown to effectively suppress organoid growth. Tumor organoids were successfully developed from primary tumors. With our optimized assay using primary tumor organoids and a multi-stage high throughput drug screening, a novel panel of epigenetic drugs that effective alone or additively with radiation was identified."

Brain Cancer • CNS Tumor • Gene Therapies • Glioblastoma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • SUV39H1

Opposing Effects of TRβ-LSD1/KDM1A Co-Regulatory Complex in Normal and Anaplastic Thyroid Cancer Cells (ATA 2024) - "LSD1/KDM1A silencing by shRNA knockdown or allosteric inhibition with SP-2509 was performed in combination with TRβ agonists. PPIN analysis revealed TRβ and ALL-1 interaction nodes that include LSD1/KDM1A... PPIN analysis revealed TRβ and ALL-1 interaction nodes that include LSD1/KDM1A. Chromatin occupancy analysis revealed overlapping genomic binding sites of TRβ and LSD1/KDM1A with a decrease in repressive histone marks around the TSS following ligand treatment. RNA sequencing showed that LSD1/KDM1A preferentially regulates downregulated TRβ target genes."

Late-breaking abstract • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

Inhibition of LSD1 Prevented Tumor Progression and Recurrence to Radioimmunotherapy in Small Cell Lung Cancer (IASLC-WCLC 2024) - "We further evaluate the anti-tumor effect of the triple therapy of RT + ICI + LSD1 inhibitor (SP2509) on SCLC...Conclusions : In our murine SCLC model, Lsd1 positive tumor cells were enriched in the recurrence stage of RT+ ICI treatment. Triple therapy of RT+ ICI + LSD1 inhibitor could delay the tumor progression and recurrence to radioimmunotherapy through upregulating the antigen presentation pathway, downregulating the EMT pathway."

IO biomarker • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer. (PubMed, Mol Carcinog) - "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."

Journal • Colorectal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • KDM1A

Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers. (PubMed, Cancer Discov) - "Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Oncology • Solid Tumor

SP2509, a specific antagonist of LSD1, exhibits antiviral properties against Porcine epidemic diarrhea virus. (PubMed, BMC Vet Res) - "Our results in vitro show that SP2509 can inhibit PEDV infection during the internalization and replication stage and revealed a role of LSD1 as a restriction factor for PEDV. These imply that LSD1 might be a target for interfering with the viral infection, and SP2509 could be developed as an effective anti-PEDV agent."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease

Inhibition of LSD1 via SP2509 attenuated the progression of rheumatoid arthritis. (PubMed, Immunol Res) - "In CIA models, SP2509 treatment ameliorated RA development, reducing the expression of pro-inflammatory cytokines and alleviating joint pathological symptoms. These findings underscore the significance of LSD1 in RA and propose the therapeutic potential of SP2509."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • KDM1A • TNFA

SP2509 functions as a novel ferroptosis inhibitor by reducing intracellular iron level in vascular smooth muscle cells. (PubMed, Free Radic Biol Med) - "Therefore, our findings indicate that SP2509 protects VSMCs from multiple stimulus-induced ferroptosis by reducing intracellular iron levels, thereby preventing lipid peroxidation and cell death. These findings suggest that SP2509 may be a promising drug to alleviate AD by reducing iron deposition and VSMC ferroptosis."

Journal • Hematological Disorders • Inflammation

A TBX2-driven signaling switch from androgen receptor to glucocorticoid receptor confers enzalutamide resistance in prostate cancer (AACR 2024) - "Importantly, we found that SP2509, an allosteric inhibitor of the demethylase-independent function of LSD1, a TBX2-interacting protein in the COREST complex, can disrupt both TBX2-LSD1 and TBX2-GR protein-protein interactions thereby uncovering a unique mode of SP2509 action in CRPC. In summary, our study identifies TBX2 as the molecular switch that drives the AR to GR signaling bypass thereby conferring enzalutamide resistance. Further, our study provides key insights into a potential therapeutic modality for targeting the AR to GR signaling switch via disruption of the TBX2-LSD1 and TBX2-GR protein-protein interactions"

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • GATA2 • NR3C1 • TBX2

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer (AACR 2024) - "Cell viability, colony formation, and apoptosis assays were used to determine the impact of KDM1A KD on sensitization of SKOV3, OVCAR8, and OVCAR5 OCa cells to cisplatin, carboplatin, and paclitaxel. The combination effect of KDM1A inhibitors (NCD38 and SP2509) and chemotherapy drugs was further determined... These results suggest that the combination of KDM1A inhibitors with chemotherapy is a viable therapeutic approach for the treatment of OCa"

Colorectal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • KDM1A

Potential role of lipophagy impairment for anticancer effects of glycolysis-suppressed pancreatic ductal adenocarcinoma cells. (PubMed, Cell Death Discov) - "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."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KDM1A

SECLIDEMSTAT TREATMENT BLOCKS THE TRANSCRIPTIONAL FUNCTION OF MULTIPLE FET-FUSION PROTEINS (CTOS 2023) - "The histone lysine specific demethylase 1 (LSD1) has been identified as a critical chromatin coregulator and inhibition with the noncompetitive inhibitor, SP-2509, has been shown to block the transcriptional function of EWS::FLI and EWS::ERG. These data indicate that seclidemstat blocks the transcriptional activity of FET-rearranged proteins in tumors other than Ewing sarcoma. This suggests LSD1 is critical co-regulator in other FET-rearranged malignancies. Our data also identify the heterogeneity in fusion-driven transcription and the response to seclidemstat, both across tumor types and with different cell lines of the same tumor type."

Ewing Sarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • DDIT3 • EWSR1 • FUS • TAF15 • WT1

Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma. (PubMed, Exp Hematol Oncol) - "The present study preclinically demonstrated that LSD1 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients and that this combination might be exploited for the treatment of other B-cell malignancies, thus extending the therapeutic impact of the project."

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • SDC1