Abstract B81: Analogues of the chromenone namoline as inhibitors of lysine specific demethylase 1 (LSD1)

Since it had been discovered in 2004, lysine-specific-demethylase 1 (LSD1) has been emphasized as a potential target for anticancer drugs. The physiological role of LSD1 is versatile which can be seen in its function in different LSD1-related protein complexes such as CoREST with the androgen receptor. Interacting with those various molecular domains, LSD1 leads to e.g. a regulation of gene expression and control of hematopoietic differentiation. So it is hardly surprising that several LSD1 inhibitors are already in clinical trials. Namoline has been identified in collaboration with other groups using a bioinformatics approach based on active site similarity and a focused library screen. This hit impairs LSD1 activity in-vitro and in-vivo and is a promising starting compound for further investigations. Our latest developed heterogeneous assay-systems are resistant against auto-fluorescence and maybe will give us further insights into biophysiological interactions between inhibitors and the targeted enzyme. Based upon on this, we report structure-activity studies of namoline and its improved analogues which lead up to a 40-fold increased potency and retained selectivity over MAO-A and B. We show that namoline and its potent analogues have antiproliferative activity in Rhabdomyosarcoma cells with slightly improved efficacy for the new analogues. Citation Format: Johannes Schulz-Fincke, Martin L. Schmitt, Luca Carlino, Tinka Haydn, Dominica Willmann, Eric Metzger, Simone Fulda, Roland Schule, Wolfgang Sippl, Manfred Jung. Analogues of the chromenone namoline as inhibitors of lysine specific demethylase 1 (LSD1). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B81.