LSD1 inhibitor, TAS1440, disrupts INSM1-LSD1 complex activating tumor-suppressive pathways via transcriptional reprogramming in neuroendocrine SCLC.

Small cell lung cancer (SCLC) is aggressive with limited treatment options, requiring new therapies. Lysine-specific histone demethylase 1 A (LSD1) maintains neuroendocrine state by repressing NOTCH/TGF-β signaling; their reactivation suppresses proliferation and induces differentiation. However, mechanisms of LSD1 inhibition and chemoresistance remain unclear. Here we developed TAS1440, a histone H3-competitive LSD1 inhibitor, using structure-based engineering to improve specificity and reduce off-target effects. Unlike irreversible inhibitors targeting the flavin adenine dinucleotide site, TAS1440 non-covalently targets the H3-binding pocket to enhance safety and efficacy. TAS1440 suppressed proliferation in INSM1/ASCL1-high SCLC-A cells and induced tumor regression in xenografts. TAS1440 acts through dual mechanisms: inhibiting LSD1 activity and disrupting LSD1-repressive complexes, remodeling histone marks and activating transcription factors INSM1 and SMAD2. These actions reprogram tumor-suppressive TGF-β/NOTCH signaling, supporting TAS1440 as epigenetic therapy for SCLC. Loss of LSD1 enzymatic activity or INSM1 knockout abrogated TAS1440 effects, defining its mode of action and chemoresistance. These findings support TAS1440 as a next-generation epigenetic therapy candidate for INSM1-high SCLC-A.