1. Covalent Peptide LSD1 Inhibitor Specifically Recognizes Cys360 in the Enzyme-Active Region.
- Author
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Luo Q, Ma Y, Liang H, Feng Y, Liu N, Lian C, Zhu L, Ye Y, Liu Z, Hou Z, Chen S, Wang Y, Dai C, Song C, Zhang M, He Z, Xing Y, Zhong W, Li S, Wu J, Lu F, Yin F, and Li Z
- Subjects
- Animals, Humans, Cell Line, Tumor, Cell Proliferation, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Histone Demethylases metabolism, Peptides pharmacology, Peptides, Cyclic pharmacology, Peptides, Cyclic therapeutic use, Lysine analogs & derivatives, Cysteine, Neoplasms
- 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.
- Published
- 2023
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