Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid as LSD1 inhibitor

Bioorg Med Chem Lett. 2019 Mar 15;29(6):844-847. doi: 10.1016/j.bmcl.2019.01.017.

Xiaowen Wang ¹, Mingbo Su ², You Li ³, Tongchao Liu ⁴, Yujie Wang ², Yabing Chen ⁵, Le Tang ⁵, Yu-Peng He ⁶, Xiaoguang Ding ⁶, Fang Yu ⁷, Jingkang Shen ⁸, Jia Li ², Yubo Zhou ⁹, Yue-Lei Chen ¹⁰, Bing Xiong ¹¹

Affiliations

1 College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
2 The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, PR China.
5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
6 College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, PR China.
7 College of Chemistry, Chemical Engineering and Environmental Engineering, Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, PR China. Electronic address: fang.yu@lnpu.edu.cn.
8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
9 The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: ybzhou@simm.ac.cn.
10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: chenyuelei@gmail.com.
11 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: bxiong@simm.ac.cn.

PMID: 30713023 DOI: 10.1016/j.bmcl.2019.01.017

Abstract

Tranylcypromine moiety extracted from LSD1 inhibitors and 6-trifluoroethyl thienopyrimidine moiety from menin-MLL1 PPI inhibitors were merged to give new chemotypes for medicinal chemistry study. Among 15 new compounds prepared in this work, some exhibited nanomolar LSD1 activity and good selectivity over MAO-A/B, low micromolar menin-MLL1 PPI inhibitory activity, as well as submicromolar MV4-11 antiprofilative activities. Intracellular LSD1 engagement of compounds with higher enzymatic and antiproliferative activities was confirmed by CD86 mRNA up-regulation experiments.

Keywords

LSD1 inhibitor; MV4-11 antiproliferative activity; Menin-MLL1 protein-protein interaction inhibitor; Structure activity relationship; Tranylcypromine.

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