Covalent Peptide LSD1 Inhibitor Specifically Recognizes Cys360 in the Enzyme-Active Region

  • J Med Chem. 2023 Nov 23;66(22):15409-15423. doi: 10.1021/acs.jmedchem.3c01549.
Qinhong Luo  1  2  3 ,  Yue Ma  2 ,  Huiting Liang  3 ,  Yuan Feng  2 ,  Na Liu  2  3 ,  Chenshan Lian  2  3 ,  Lizhi Zhu  1  2 ,  Yuxin Ye  3 ,  Zhihong Liu  3 ,  Zhanfeng Hou  2 ,  Sijin Chen  2 ,  Yaqi Wang  2 ,  Chuan Dai  1  3 ,  Chunli Song  3 ,  Min Zhang  3 ,  Zhipeng He  3 ,  Yun Xing  3 ,  Wanjin Zhong  2 ,  Shuiming Li  4 ,  Jianlong Wu  1 ,  Fei Lu  2 ,  Feng Yin  2  3 ,  Zigang Li  2  3
Affiliations
  • 1. Department of Pharmacy, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
  • 2. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 3. Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen 518118, China.
  • 4. Shenzhen Key Laboratory of Microbiology and Gene Engineering, Shenzhen University, Shenzhen 518060, China.
PMID: 37922441 DOI: 10.1021/acs.jmedchem.3c01549
Abstract

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target, especially in Cancer treatment. Despite several LSD1 inhibitors being discovered for the cofactor pocket, none are FDA-approved. We aimed to develop stabilized peptides for irreversible LSD1 binding, focusing on unique cysteine residue Cys360 in LSD1 and SNAIL1. We created LSD1 C360-targeting peptides, like cyclic peptide S9-CMC1, using our Cysteine-Methionine cyclization strategy. S9-CMC1 effectively inhibited LSD1 at the protein level, as confirmed by MS analysis showing covalent bonding to Cys360. In cells, S9-CMC1 inhibited LSD1 activity, increasing H3K4me1 and H3K4me2 levels, leading to G1 cell cycle arrest and Apoptosis and inhibiting cell proliferation. Remarkably, S9-CMC1 showed therapeutic potential in A549 xenograft animal models, regulating LSD1 activity and significantly inhibiting tumor growth with minimal organ damage. These findings suggest LSD1 C360 as a promising site for covalent LSD1 inhibitors' development.

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