Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity. •LSD1 is important in oncogenesis, suggesting it may serve as a therapeutic target•GSK2879552 is a potent, selective, oral, mechanism-based inactivator of LSD1•GSK2879552 has an antitumor effect in SCLC cells in vitro and in vivo•DNA hypomethylation of a signature probe set predicts sensitivity to GSK2879552 Mohammad et al. identify the orally available lysine demethylase 1 (LSD1)-selective inhibitor GSK2879552 and find unexpectedly that some small cell lung cancer cell lines are sensitive to LSD1 inhibition. Mohammad et al. further identify a potential biomarker predictive of response to GSK2879552.