2. Academic Validation
  3. Covalent Peptide LSD1 Inhibitor Specifically Recognizes Cys360 in the Enzyme-Active Region

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

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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