Abstract
Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors of LSD1 are expected to be useful for the treatment of several cancers. Reversible inhibitors of LSD1 with submicromolar inhibitory potency have recently been reported, but their exact binding modes are poorly understood. In this study, we synthesized a recently reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile, which bears a 4-piperidinylmethoxy group, a 4-methylphenyl group, and a 4-cyanophenyl group on a pyridine ring, and determined the crystal structure of LSD1 in complex with this inhibitor at 2.96 Å. We observed strong electron density for the compound, showing that its cyano group forms a hydrogen bond with Lys661, which is a critical residue in the lysine demethylation reaction located deep in the catalytic center of LSD1. The piperidine ring interacts with the side chains of Asp555 and Asn540 in two conformations, and the 4-methylphenyl group is bound in a hydrophobic pocket in the catalytic center. Our elucidation of the binding mode of this compound can be expected to facilitate the rational design of more-potent reversible LSD1 inhibitors.
Highlights
Methylation of histone lysine residues modulates gene expression, activating or inactivating it depending on the lysine site and degree of methylation [1]
LSD1CoREST in complex complex with with 4-[5-(piperidin4-[5-(piperidinIn this paper, we present the crystal structure of
The electron density map after molecular replacement clearly revealed the bound inhibitor, which has three branches extending from the pyridine ring at the center of the molecule: a 4-piperidinylmethoxy group, a 4-methylphenyl group, and a 4-cyanophenyl group
Summary
Methylation of histone lysine residues modulates gene expression, activating or inactivating it depending on the lysine site and degree of methylation [1]. [8,9,10].LSD1-selective involved in acute myeloid leukemia and glioblastoma inhibitors are expected to serve as therapeutic agents for these diseases. Information obtained from from crystal structures of LSD1 or the LSD1CoREST complex, bound. 2-PCPAand and its its derivatives crystal structures of LSD1 or the toto2-PCPA The crystal structures bound to these compounds that molecules bind molecules to the negatively entrancecharged of the substrate-binding cavity of LSD1 in cavity multiple the polymyxin bind tocharged the negatively entrance of the substrate-binding of rotated orientations. Binding modes the newly inhibitors were validated on complexes the basis ofwith crystal structures of the crystal with structure of LSD1CoREST withthe noncovalently bound tetrahydrofolate has been their complexes.
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