seclidemstat (SP2577)

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.

P1/2, N=44, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Sep 2025 --> Sep 2027

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.

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.

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.

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.

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