2. Academic Validation
  3. Structure-Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors

Structure-Activity Relationship Study of Indolin-5-yl-cyclopropanamine Derivatives as Selective Lysine Specific Demethylase 1 (LSD1) Inhibitors

  • J Med Chem. 2022 Mar 10;65(5):4335-4349. doi: 10.1021/acs.jmedchem.1c02156.
Chunpu Li 1 2 3,  Mingbo Su 4,  Wei Zhu 1,  Weijuan Kan 1,  Tianpeng Ge 1 5,  Gaoya Xu 1,  Shuni Wang 1,  Li Sheng 1,  Feng Gao 1,  Yunfei Ye 6,  Jiang Wang 1 2,  Yubo Zhou 1 4 7 3,  Jia Li 1 4 7 2 3,  Hong Liu 1 4 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Qixia District, Nanjing 210023, China.
  • 5 College of Pharmacy, Weifang Medical University, Weifang 261053, China.
  • 6 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Zhongshan, Guangdong 528400, China.
PMID: 35200034 DOI: 10.1021/acs.jmedchem.1c02156
Abstract

LSD1 is identified as an essential drug target, which is closely correlated to the development of several tumor types. In this work, on the basis of comprehensive analysis of the binding site of LSD1 and other FAD-dependent enzymes, a novel series of potent and selective LSD1 inhibitors were designed by incorporation of privileged indoline scaffold strategies. Representative compound 7e (LSD1; IC50 = 24.43 nM, selectivity over LSD2 and MAOs of >200- and 4000-fold) possessed selective antiproliferative activities against MV-4-11 cell lines. Further study indicates that 7e could activate CD86 expression (EC50 = 470 nM) and induce differentiation of AML cell lines. More importantly, compound 7e demonstrated an acceptable oral PK profile and good in vivo antitumor efficacy with a T/C value of 30.89% in an MV-4-11 xenograft mouse model. Collectively, this work provides a promising lead compound for the development of novel LSD1 inhibitors for the treatment of AML.

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