Structure–Activity Relationship and In Silico Evaluation of cis- and trans-PCPA-Derived Inhibitors of LSD1 and LSD2

[Image: see text] trans-2-Phenylcycloproylamine (trans-PCPA) has been used as the scaffold to develop covalent-binding inhibitors against lysine-specific demethylase 1 (LSD1/KDM1A), a therapeutic target for several cancers. However, the effects of different structural moieties on the inhibitory activity, selectivity, and reactivity of these derivatives, including the cis isomers, against LSD1 and its paralogue LSD2/KDM1B are not fully understood. Here we synthesized 65 cis- and trans-PCPA derivatives and evaluated their inhibitory activity against LSD1 and LSD2. One of the derivatives, 7c (cis-4-Br-2,5-F(2)-PCPA; S1024), inhibited LSD1 and LSD2 with K(i) values of 0.094 μM and 8.4 μM, respectively, and increased the level of dimethylated histone H3 at K4 in CCRF-CEM cells. A machine learning-based regression model (Q(2) = 0.61) to predict LSD1-inhibitory activity was also constructed and showed a good prediction accuracy (R(2) = 0.81) for 12 test-set compounds, including 7c. The present methodology would be useful when designing covalent-binding inhibitors for other enzymes.