seclidemstat (SP2577)

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.

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

P1/2, N=44, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P1, N=50, Active, not recruiting, Salarius Pharmaceuticals, LLC | Recruiting --> Active, not recruiting

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.

P1/2, N=44, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2023 --> Sep 2025 | Trial primary completion date: Sep 2023 --> Sep 2025

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.

P1/2, N=44, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

The combination of seclidemstat with azacitidine seems safe at the current dose levels and shows initial signs of potential activity. Further enrollment and follow up continues to further explore this combination.

P1/2, N=44, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023

In GBM cell lines, we identified an upregulation of genes associated with cell death, regulation of cell proliferation, and regulation of intracellular signaling upon both LSD1 KD and LSD1 inhibition using tranylcypromine treatment. Additional, more selective, pharmacological inhibitors of LSD1 (GSK-LSD1, RN-1 and SP-2577) in vitro had differential responses in the GSCs that were more varied, and responses were dependent on the specific LSD1 inhibitor and GSC line...Finally, the resistant-associated genes were present in exome sequencing data from GBM patients where they showed an inverse relationship with LSD1 expression. Future studies will focus on designing combination therapies with LSD1 inhibitors that will enhance their effects and overcome resistance associated with treatment by targeting pathways associated with the genes we have uncovered.

Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS)...Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients...Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.

P1, N=0, Withdrawn, HonorHealth Research Institute | N=30 --> 0 | Not yet recruiting --> Withdrawn

P1, N=50, Recruiting, Salarius Pharmaceuticals, LLC | Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Sep 2021 --> Sep 2023

Seclidemstat has shown encouraging activity among advanced sarcoma patients with a manageable safety profile. Preliminary clinical data supports further exploration in FET-translocated sarcoma as a single agent in an ongoing phase 2 trial (ClinicalTrials.gov Identifier: NCT03600649)

P1/2, N=44, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

There were no tumor regressions or consistent changes in dimethyl histone H3(K4), HOXM1, DAX1, c-MYC and N-MYC, or tumor histology/differentiation. SP-2577 has limited activity against these pediatric sarcoma models at the dose and schedule evaluated.

P1, N=30, Not yet recruiting, HonorHealth Research Institute | Trial completion date: Jun 2023 --> Jun 2024 | Initiation date: Dec 2020 --> Aug 2021 | Trial primary completion date: Dec 2022 --> Dec 2023

Our data support the validity of the arrayed CRISPR screening to identify new therapeutic strategies in ES, and highlights the potential for Ruxolitinib or Dasatinib treatment in combination with SP-2577 in ES patients.

P1/2, N=44, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=30, Not yet recruiting, HonorHealth Research Institute

We found that SP-2577 stimulated IFN-dependent anti-tumor immunity in SCCOHT and promoted the expression of PD-L1 in both SCCOHT and OCCC. Together, these findings suggest that the combination therapy of SP-2577 with checkpoint inhibitors may induce or augment immunogenic responses of SWI/SNF-mutated ovarian cancers and warrants further investigation.