Structure-Activity Relationship and In Silico Evaluation of cis- and trans-PCPA-Derived Inhibitors of LSD1 and LSD2.
Structure-Activity Relationship and In Silico Evaluation of cis- and trans-PCPA-Derived Inhibitors of LSD1 and LSD2.
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DOI：
10.1021/acsmedchemlett.2c00294
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发表时间：
2022-09-08
影响因子：
4.2
通讯作者：
Umehara, Takashi
中科院分区：
文献类型：
--
作者：
Niwa, Hideaki;Watanabe, Chiduru;Sato, Shin;Harada, Toshiyuki;Watanabe, Hisami;Tabusa, Ryo;Fukasawa, Shunsuke;Shiobara, Ayane;Hashimoto, Tomoko;Ohno, Osamu;Nakamura, Kana;Tsuganezawa, Keiko;Tanaka, Akiko;Shirouzu, Mikako;Honma, Teruki;Matsuno, Kenji;Umehara, Takashi
反式-2-苯基环丙基胺（trans-PCPA）已被用作支架开发针对赖氨酸特异性脱甲基酶1（LSD 1/KDM 1A）的共价结合抑制剂，LSD 1/KDM 1A是几种癌症的治疗靶点。然而，不同结构部分对这些衍生物（包括顺式异构体）对LSD 1及其paraffin LSD 2/KDM 1B的抑制活性、选择性和反应性的影响尚未完全了解。在这里，我们合成了65顺式和反式PCPA衍生物，并评估其对LSD 1和LSD 2的抑制活性。其中一种衍生物7 c（cis-4-Br-2，5-F2-PCPA; S1024）抑制LSD 1和LSD 2，Ki值分别为0.094 μM和8.4 μM，并增加CCRF-CEM细胞K4处二甲基化组蛋白H3的水平。还构建了基于机器学习的回归模型（Q2 = 0.61）来预测LSD 1抑制活性，并且对12个测试集化合物（包括7 c）显示出良好的预测准确性（R2 = 0.81）。本方法在设计其他酶的共价结合抑制剂时将是有用的。
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 Ki 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 (Q2 = 0.61) to predict LSD1-inhibitory activity was also constructed and showed a good prediction accuracy (R2 = 0.81) for 12 test-set compounds, including 7c. The present methodology would be useful when designing covalent-binding inhibitors for other enzymes.
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影响因子：
15
作者：
Binda, Claudia;Valente, Sergio;Mai, Antonello
通讯作者：
Mai, Antonello
影响因子：
3.7
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Niwa H;Umehara T
通讯作者：
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通讯作者：
Mai, Antonello