Small Molecule Inhibitors of Lysine Specific Demethylase 1 Used for Cancer Therapeutics

Lysine Specific Demethylase 1 (LSD1) is an enzyme that was recently found to have an effect on gene expression through epigenetics. Over-expression of LSD1 has been observed in many tumor cell lines which has made it an active target for cancer therapeutics. The original compound found to inhibit LSD1, C9, needs an improvement in solubility with regards to toxicity for In-Vivo testing. We propose the removal of aromatic halogens combined with the addition of electron donating substituents will yield higher solubility along with increased potency towards inhibiting LSD1. In order in increase solubility while maintaining potency we need to design derivatives of C9, synthesize and confirm LSD1 inhibition. To achieve product formation in the compound synthesis the reaction was microwaved, extracted, rotovapped, and placed on a high vac. After a sample was taken to run an NMR to confirm the product formation along with TLC, LCMS and UPLC. During the synthesis the reaction first underwent a Nitrile reduction to primary amine. Next carbothioamide intermediate followed immediately by cyclization using hydrazine and Electrophilic Aromatic Substitution (EAS) with phenol. The compound had issues with synthesis as the electron withdrawing group did not allow for proper EAS coupling and there was a tough extraction as DMSO was used as solvent. In order to achieve an increased solubility the reaction needs to occur at a lower temperature for a longer time. This is not only true for the two compounds worked on in this project but for many other compounds involving LSD1