seclidemstat (SP2577) / Salarius - LARVOL DELTA

NCI-2020-14163: Seclidemstat and Azacitidine for the Treatment of Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1/2 | N=44 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Sep 2025 ➔ Sep 2027 | Trial primary completion date: Sep 2025 ➔ Sep 2027

Trial completion date • Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • NRAS • RUNX1 • SETBP1 • TP53

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

Synthetic and structure-activity studies of SP2577 and TCP towards LSD1 targeting PROTACs. (PubMed, RSC Med Chem) - "No LSD1 degraders were identified in HCT116 cells, however two TCP analogues functionalised from the phenyl ring with an aklyl and PEG linker in combination with a VHL ligand demonstrated potent LSD1 inhibition in vitro in the HDAC1-CoREST-LSD1 complex (43 nM and 63 nM respectively). Our findings provide important SAR data towards LSD1 PROTACs."

Journal • Targeted Protein Degradation • HDAC1 • 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

Salarius Pharmaceuticals’ Seclidemstat Demonstrates Supporting Role in Inhibiting Validated Oncology Target LSD1 in Two Recently Published Studies (Yahoo Finance) - "Salarius Pharmaceuticals, Inc...announces that two animal studies recently published in peer-reviewed journals provide additional insight into the role of inhibiting lysine-demethylase 1 (LSD1 or KDM1A), a well-validated target in hematologic and solid tumors."

Preclinical • Oral Cancer • Squamous Cell Carcinoma

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

Salarius Pharmaceuticals Reports 2024 Financial Results and Provides Business Update (GlobeNewswire) - "Updates expected later this year from the MD Anderson Cancer Center (MDACC) investigator-initiated Phase 1/2 clinical trial of seclidemstat in combination with azacitidine to treat hematologic cancers."

P1/2 data • Hematological Malignancies

Leveraging non-enzymatic functions of LSD1 for novel therapeutics. (PubMed, Trends Pharmacol Sci) - "Only one allosteric inhibitor (SP-2577) and two nonproteolysis-targeting chimera (PROTAC) LSD1 degraders (BEA-17 and UM171), which target its enzyme-independent functions, have entered clinical assessment. Given the limited exploration of therapeutic strategies targeting the non-enzymatic functions of LSD1, in this opinion, we summarize current insights into its biological roles and structural characteristics. We also highlight potential therapeutic interventions targeting the non-enzymatic functions of LSD1, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and small-molecule degraders, and discuss challenges and future directions in drug discovery targeting these functions."

Journal • Review • Targeted Protein Degradation

Histone lysine demethylase 1A inhibitors, seclidemstat and tranylcypromine, induce astrocytogenesis in rat neural stem cells. (PubMed, Biochem Biophys Res Commun) - "Therefore, we show that the KDM1A inhibitors, SP-2577 and TCP, induce astrocytogenesis in rat NSCs. These findings suggest that KDM1A is a target for regulating NSCs fate and provide insights into the molecular mechanisms underlying neurodevelopmental processes and epigenetics."

Journal • Preclinical • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • FAP • FGF2 • GFAP • IL6 • KDM1A • LIF • STAT3 • TUBB3

Salarius Pharmaceuticals Announces Patient Enrollment to Resume in Investigator-initiated Phase 1/2 Clinical Trial Using Seclidemstat with Azacitidine to Treat Hematologic Cancers (GlobeNewswire) - "Salarius Pharmaceuticals, Inc...announces that patient enrollment will resume in the investigator-initiated Phase 1/2 clinical trial evaluating seclidemstat in combination with azacitidine for the treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The trial is being conducted at the University of Texas MD Anderson Cancer Center (MDACC) and is listed as recruiting on clinical trials.gov – trial NCT04734990....MDACC has addressed the FDA’s questions, and the partial clinical hold has been lifted."

Enrollment status • Chronic Myelomonocytic Leukemia • Myelodysplastic Syndrome

Salarius reports serious adverse event in drug trial (Investing.com) - "Salarius Pharmaceuticals, Inc...disclosed today a significant development regarding its clinical trial for the drug seclidemstat. The company, in a recent filing with the Securities and Exchange Commission (SEC), announced that a patient experienced a grade 4 adverse event during a clinical trial evaluating seclidemstat in combination with azacitidine...Following the adverse event, reported to the company on Tuesday, the U.S. Food and Drug Administration (FDA) has placed the clinical trial on a partial clinical hold. This decision prohibits the enrollment of new patients but allows those currently in the trial to continue their treatment if they are receiving benefits from the therapy."

Trial suspension • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

PHASE I/II STUDY OF SECLIDEMSTAT, AN LSD1 INHIBITOR, IN COMBINATION WITH AZACITIDINE FOR PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND CHRONIC MYELOMONOCYTIC LEUKEMIA (EHA 2024) - P1/2 | "Five(36%) pts had received prior venetoclax therapy and 2 (14%) had prior allogeneic stem-cell transplant (allo-SCT). The combination of seclidemstat with azacitidine seems safe at the current dose levelsand shows initial signs of potential activity."

Clinical • Combination therapy • P1/2 data • Acute Kidney Injury • Atrial Fibrillation • Bone Marrow Transplantation • Cardiovascular • Cerebral Hemorrhage • Chronic Myelomonocytic Leukemia • CNS Disorders • Constipation • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Nephrology • Oncology • Pneumonia • Renal Disease • Respiratory Diseases • Transplantation

Clinical Data on Salarius Pharmaceuticals’ Seclidemstat in Patients with MDS and CMML Presented at the 2024 European Hematology Association Annual Meeting (GlobeNewswire) - P1/2 | N=44 | NCT04734990 | "Salarius Pharmaceuticals, Inc...announced that investigators at the University of Texas MD Anderson Cancer Center’s Leukemia department presented clinical data on seclidemstat in patients with MDS and CMML at the 2024 European Hematology Association (EHA) Hybrid Congress....As presented at EHA, of the 14 evaluable patients for efficacy, 6 (43%) had an objective response including 1 complete response, 3 marrow complete responses, 1 marrow complete response plus hematological improvement and 1 hematologic improvement. The median overall survival was 18.5 months (95% CI, range 6.1-30.9 months), median event-free survival was 7.2 months (95% CI, range 6.3-8.2 months) and median follow-up time was 18.9 months (95% CI, range 0-48 months) from treatment initiation."

P1/2 data • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates. (PubMed, Biochemistry) - "Here, the inhibition kinetics on the H3K4me2 peptide and nucleosome substrates was examined, comparing the rates of demethylation in the presence of reversible [CC-90011 (PD) and SP-2577 (SD)] and irreversible [ORY-1001 (ID) and tranylcypromine (TCP)] inhibitors. These data show that SP-2577 is not an LSD1 enzyme inhibitor, although the drug may function independent of demethylation due to its cytotoxic selectivity in TC-32 cells. Taken together, this work highlights the pitfalls of using coupled assays to ascribe a drug's mode of action, emphasizes the use of physiologically relevant substrates in epigenetic drug targeting strategies, and provides insight into the development of substrate-selective inhibitors of LSD1."

Epigenetic controller • Journal • Acute Myelogenous Leukemia • Ewing Sarcoma • Hematological Malignancies • Leukemia • Lung Cancer • Oncology • Sarcoma • Small Cell Lung Cancer • Solid Tumor

Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules. (PubMed, Int J Mol Sci) - "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."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • CDH2 • GFAP • KDM1A • PTEN • TGFB1

Salarius Pharmaceuticals Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Business Update (GlobeNewswire) - "Patient Enrollment Resumed in the Investigator-initiated Phase 1/2 Clinical Trial of Seclidemstat in Combination with Azacitidine to Treat Hematologic Cancers....we look forward to clinical trial updates later this year....The Company’s Ewing sarcoma Phase 1/2 study is not currently enrolling patients, but previously enrolled patients continue to be followed."

P1/2 data • Trial status • Ewing Sarcoma • Hematological Malignancies • Oncology • Sarcoma • Solid Tumor

Salarius Provides Update on Strategic Review Process and Plans to Support Ongoing Seclidemstat Clinical Trials by Further Reducing Expenses (GlobeNewswire) - "Salarius Pharmaceuticals...announced that its Board of Directors is implementing a series of additional cost-savings measures designed to extend Salarius’ expected cash runway into the first half of 2025. These measures will allow Salarius to support the generation of additional clinical data for seclidemstat in the ongoing MD Anderson Cancer Center (MDACC) investigator-initiated Phase 1/2 clinical trial in hematologic cancers and Salarius’ Phase 1/2 trial in Ewing sarcoma....The cost-savings measures also include reducing operating expenses and reducing the cash compensation payable to the Company’s non-employee directors beginning in the second quarter of 2024."

Commercial • Ewing Sarcoma • Hematological Malignancies

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy. (PubMed, J Med Chem) - "Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577)...LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents."

Combination therapy • Journal • Review • Oncology

Investigator-initiated Phase 1/2 Clinical Trial Using Salarius Pharmaceuticals’ Seclidemstat in Combination with Azacitidine to Treat Hematologic Cancers Resumes Patient Enrollment (GlobeNewswire) - P1/2 | N=44 | NCT04734990 | "Salarius Pharmaceuticals, Inc...announces that the hematologic cancer Phase 1/2 clinical trial being conducted at the University of Texas MD Anderson Cancer Center (MDACC or MD Anderson) is now listed as active and recruiting on clinical trials.gov – trial NCT04734990. Salarius also announces that an additional Ewing sarcoma patient treated with seclidemstat, topotecan and cyclophosphamide (TC) has achieved a partial response as demonstrated by at least a 30% decrease in the sum of diameters of the patient’s target lesions, bringing the objective response rate (ORR) in Ewing sarcoma first-relapse patients to 60%, with a 60% disease control rate (DCR)."

P1/2 data • Trial status • Ewing Sarcoma • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Sarcoma

SALA-002-EW16: Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Salarius Pharmaceuticals, LLC

Trial completion date • Trial primary completion date • Ewing Sarcoma • Fibrosarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • EWSR1

Seclidemstat and Azacitidine for the Treatment of Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P1/2 | N=44 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Recruiting

Enrollment open • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • NRAS • RUNX1 • SETBP1 • TP53

SALA-002-EW16: Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Salarius Pharmaceuticals, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Ewing Sarcoma • Fibrosarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • EWSR1

Salarius Completes FDA Type B Meeting for Seclidemstat Ewing Sarcoma Development Program (GlobeNewswire) - "Salarius Pharmaceuticals, Inc...announces that it participated in a Type B End-of-Phase 2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA) to receive guidance regarding the development program for seclidemstat to treat Ewing sarcoma. The Company has received the final meeting minutes and is amending the current clinical trial protocol to reflect guidance agreed to with FDA during the EOP2 meeting....Based on the advice received from the FDA and the new clinical data Salarius shared during the meeting process, Salarius is preparing an amendment to the Ewing sarcoma clinical trial protocol and plans to submit the amended protocol in the coming months."

Clinical protocol • FDA event • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

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

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics. (PubMed, ACS Chem Biol) - "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)...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."

Journal • Review • Oncology • SNAI1