Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1)

Histone demethylase
LSDl (KDMlA) belongs to the flavin adenine
dinucleotide (FAD) dependent family of monoamine oxidases and is vital
in regulation of mammalian biology. Dysregulation and overexpression
of LSD1 are hallmarks of a number of human diseases, particularly
cancers that are characterized as morphologically poorly differentiated.
As such, inhibitors of LSD1 have potential to be beneficial as a cancer
therapy. The most clinically advanced inhibitors of LSDl are covalent
inhibitors derived from tranylcypromine (TCP). Herein, we report the
discovery of a novel series of reversible and selective LSDl inhibitors.
Exploration of structure–activity relationships (SARs) and
optimization of ADME properties resulted in the identification of
clinical candidate CC-90011. CC-90011 exhibits potent on-target induction
of cellular differentiation in acute myeloid leukemia (AML) and small
cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived
xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials
in patients with first line, extensive stage SCLC (ClinicalTrials.gov
identifier: NCT03850067).