Histone demethylase LSDl (KDMlA) belongs to the FAD dependent family of monoamine oxidases and is vital in regulation of mammalian biology. However, overexpression of LSDl is a hallmark of a number of human diseases, including cancer. To date, the most advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of novel series of reversible and selective LSDl inhibitors. SAR exploration and optimization of challenging ADME properties resulted in the discovery of clinical candidate CC90011. The clinical candidate exhibits potent on-target cellular activities and robust tumor growth inhibition in AML and SCLC xenograft models.

Discovery of potent reversible inhibitors of LSD1

2019 Fall National Meeting

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