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

Hideaki Niwa; Chiduru Watanabe; Shin Sato; Toshiyuki Harada; Hisami Watanabe; Ryo Tabusa; Shunsuke Fukasawa; Ayane Shiobara; Tomoko Hashimoto; Osamu Ohno; Kana Nakamura; Keiko Tsuganezawa; Akiko Tanaka; Mikako Shirouzu; Teruki Honma; Kenji Matsuno; Takashi Umehara

doi:10.1021/acsmedchemlett.2c00294

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

ACS Med Chem Lett. 2022 Aug 18;13(9):1485-1492. doi: 10.1021/acsmedchemlett.2c00294. eCollection 2022 Sep 8.

Authors

Hideaki Niwa^{1

2}, Chiduru Watanabe³, Shin Sato^{1

2}, Toshiyuki Harada³, Hisami Watanabe^{1

2}, Ryo Tabusa⁴, Shunsuke Fukasawa⁴, Ayane Shiobara⁴, Tomoko Hashimoto⁴, Osamu Ohno⁴, Kana Nakamura², Keiko Tsuganezawa², Akiko Tanaka², Mikako Shirouzu², Teruki Honma³, Kenji Matsuno^{4

5}, Takashi Umehara^{1

2}

Affiliations

¹ Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
² Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
³ Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
⁴ Laboratory of Medicinal Chemistry, Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano, Hachioji, Tokyo 192-0015, Japan.
⁵ Department of Pharmacy, Faculty of Pharmacy, Yasuda Women's University, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan.

Abstract

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-F₂-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.