Lysine-specific histone demethylase 1 (LSD1) (also known as KDM1) is a member of a broad family of monoamine oxidases and is encoded by the KDM1A gene. However, LSD1 requires the flavin adenine dinucleotide (FAD) as a cofactor to catalyze demethylase activity. For example, LSD1 catalyzes demethylation at H3K4me1/2 and H3K9me1/2. And it also catalyzes demethylation of nonhistone protein p53 and DNMT1. The dysregulation and overexpression of LSD1 are associated with a variety of cancer types, especially cancers that are characterized as morphologically poorly differentiated. As such, the abnormal dysregulation of LSD1 leads to differentiation arrest in both hematological tumors and solid tumors, making it an attractive target for cancer therapy.

CC-90011 is a potent, selective, reversible and orally active lysine specific demethylase-1 (LSD1; KDM1A) inhibitor. However, CC-90011 is less enzymatic inhibition against LSD2, MOA-A, and MAO-B. In addition, CC-90011 induces acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cells differentiation. In THP-1 cells, CC-90011 induces of on-target cellular differentiation marker CD11b. Moreover, CC-90011 exhibits anti-proliferative activity in AML kasumi-1 cells, and no effect in normal human fibroblasts (IMR-90).

Young K Chen et al. have confirmed that CC-90011 has excellent on-target in vitro activity and pharmacokinetic properties. In H1417 SCLC xenograft and SCLC PDX model, CC-90011 treatment significantly inhibits tumor growth in mice.

To sum up, CC-90011, a highly effective and orally active LSD1 inhibitor, providing a novel differentiation strategy for the treatment of neuroendocrine tumors and AML.