Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD1

ACS Omega
Jie YangJan Kihlberg

Abstract

Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme which regulates the methylation of Lys4 of histone 3 (H3) and is overexpressed in certain cancers. We used structures of H3 substrate analogues bound to LSD1 to design macrocyclic peptide inhibitors of LSD1. A linear, Lys4 to Met-substituted, 11-mer (4) was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent (Ki = 2.3 μM) than 4. Linear and macrocyclic peptides exhibited unexpected differences in structure-activity relationships for interactions with LSD1, indicating that they bind LSD1 differently. This was confirmed by the crystal structure of 31 in complex with LSD1-CoREST1, which revealed a novel binding mode at the outer rim of the LSD1 active site and without a direct interaction with FAD. NMR spectroscopy of 31 suggests that macrocyclization restricts its solution ensemble to conformations that include the one in the crystalline complex. Our results provide a solid basis for the design of optimized reversible LSD1 inhibitors.

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Citations

Jan 18, 2021·Drug Discovery Today·Arne Christian Rufer
Feb 14, 2021·European Journal of Medicinal Chemistry·Dong-Jun FuBin Yu
Feb 24, 2021·Journal of Medicinal Chemistry·Xing-Jie DaiHong-Min Liu
Apr 5, 2021·The Journal of Biological Chemistry·Mareike WiedmannJames Inglese
Jul 16, 2021·RSC Medicinal Chemistry·Quynh Ngoc VuYu Heng Lau
Jun 20, 2020·Journal of Chemical Information and Modeling·Anna S KamenikKlaus R Liedl
Sep 16, 2020·Journal of Medicinal Chemistry·Xing-Jie DaiHong-Min Liu

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Datasets Mentioned

BETA
BC051003.1

Methods Mentioned

BETA
biosensor
chip
Assay
NMR
X-ray
size-exclusion chromatography
chips
fluorescence assay

Software Mentioned

CoREST
AIMLESS
CCP4
Molecular Operating Environment ( MOE
Protein Preparation Wizard
MMFF94x
Phenix
NMRPipe
Schrödinger Suite
gnuplot

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