Tranylcypromine and 6-trifluoroethyl thienopyrimidine hybrid as LSD1 inhibitor

Xiaowen Wang; Mingbo Su; You Li; Tongchao Liu; Yujie Wang; Yabing Chen; Le Tang; Yu-Peng He; Xiaoguang Ding; Fang Yu; Jingkang Shen; Jia Li; Yubo Zhou; Yue-Lei Chen; Bing Xiong

doi:10.1016/j.bmcl.2019.01.017

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. Epub 2019 Jan 18.

Authors

Xiaowen Wang¹, Mingbo Su², You Li³, Tongchao Liu⁴, Yujie Wang², Yabing Chen⁵, Le Tang⁵, Yu-Peng He⁶, Xiaoguang Ding⁶, Fang Yu⁷, Jingkang Shen⁸, Jia Li², Yubo Zhou⁹, Yue-Lei Chen¹⁰, Bing Xiong¹¹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
B7-2 Antigen / genetics
Cell Line, Tumor
Histone Demethylases / antagonists & inhibitors*
Humans
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
RNA, Messenger / metabolism
Thiophenes / chemical synthesis
Thiophenes / pharmacology
Tranylcypromine / analogs & derivatives
Tranylcypromine / chemical synthesis
Tranylcypromine / pharmacology*
Up-Regulation / drug effects

Substances

Antineoplastic Agents
B7-2 Antigen
CD86 protein, human
Monoamine Oxidase Inhibitors
Pyrimidines
RNA, Messenger
Thiophenes
Tranylcypromine
Histone Demethylases
Monoamine Oxidase
monoamine oxidase A, human
KDM1A protein, human