Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(-tolyl)pyridin-3-yl]benzonitrile

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2018 Jun 29

PMID 29949906

Citations 9

Authors

Hideaki Niwa

Shin Sato

Tomoko Hashimoto

Kenji Matsuno

Takashi Umehara

Affiliations

Soon will be listed here.

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-(-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.

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References

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Baker N, Sept D, Joseph S, Holst M, McCammon J . Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A. 2001; 98(18):10037-41. PMC: 56910. DOI: 10.1073/pnas.181342398. View

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

Morera L, Lubbert M, Jung M . Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics. 2016; 8:57. PMC: 4877953. DOI: 10.1186/s13148-016-0223-4. View

Carnesecchi J, Forcet C, Zhang L, Tribollet V, Barenton B, Boudra R . ERRα induces H3K9 demethylation by LSD1 to promote cell invasion. Proc Natl Acad Sci U S A. 2017; 114(15):3909-3914. PMC: 5393192. DOI: 10.1073/pnas.1614664114. View

Suva M, Rheinbay E, Gillespie S, Patel A, Wakimoto H, Rabkin S . Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014; 157(3):580-94. PMC: 4004670. DOI: 10.1016/j.cell.2014.02.030. View

Sartori L, Mercurio C, Amigoni F, Cappa A, Faga G, Fattori R . Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration. J Med Chem. 2017; 60(5):1673-1692. DOI: 10.1021/acs.jmedchem.6b01018. View

Metzger E, Wissmann M, Yin N, Muller J, Schneider R, Peters A . LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005; 437(7057):436-9. DOI: 10.1038/nature04020. View

10.

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

11.

Niwa H, Umehara T . Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases. Epigenetics. 2017; 12(5):340-352. PMC: 5453194. DOI: 10.1080/15592294.2017.1290032. View

12.

Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R, Karytinos A . Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc. 2010; 132(19):6827-33. DOI: 10.1021/ja101557k. View

13.

Wu F, Zhou C, Yao Y, Wei L, Feng Z, Deng L . 3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1. J Med Chem. 2015; 59(1):253-263. PMC: 4878443. DOI: 10.1021/acs.jmedchem.5b01361. View

14.

Vianello P, Sartori L, Amigoni F, Cappa A, Faga G, Fattori R . Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship. J Med Chem. 2017; 60(5):1693-1715. DOI: 10.1021/acs.jmedchem.6b01019. View

15.

Harris W, Huang X, Lynch J, Spencer G, Hitchin J, Li Y . The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012; 21(4):473-87. DOI: 10.1016/j.ccr.2012.03.014. View

16.

Adams P, Afonine P, Bunkoczi G, Chen V, Davis I, Echols N . PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):213-21. PMC: 2815670. DOI: 10.1107/S0907444909052925. View

17.

Mould D, McGonagle A, Wiseman D, Williams E, Jordan A . Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date. Med Res Rev. 2014; 35(3):586-618. DOI: 10.1002/med.21334. View

18.

Shi Y, Lan F, Matson C, Mulligan P, Whetstine J, Cole P . Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004; 119(7):941-53. DOI: 10.1016/j.cell.2004.12.012. View

19.

Schenk T, Chen W, Gollner S, Howell L, Jin L, Hebestreit K . Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012; 18(4):605-11. PMC: 3539284. DOI: 10.1038/nm.2661. View

20.

Forneris F, Binda C, Adamo A, Battaglioli E, Mattevi A . Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem. 2007; 282(28):20070-4. DOI: 10.1074/jbc.C700100200. View