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Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-Ylmethoxy)-2-(P-Tolyl) Pyridin-3-Yl]Benzonitrile

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Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-Ylmethoxy)-2-(P-Tolyl) Pyridin-3-Yl]Benzonitrile molecules Article Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl) pyridin-3-yl]benzonitrile Hideaki Niwa 1 ID , Shin Sato 1, Tomoko Hashimoto 2, Kenji Matsuno 2 and Takashi Umehara 1,* ID 1 Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research (BDR), 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan; [email protected] (H.N.); [email protected] (S.S.) 2 Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano, Hachioji, Tokyo 192-0015, Japan; [email protected] (T.H.); [email protected] (K.M.) * Correspondence: [email protected]; Tel.: +81-45-503-9457 Received: 28 May 2018; Accepted: 22 June 2018; Published: 26 June 2018 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. Keywords: chromatin; epigenetics; histone demethylase; protein-inhibitor complex; crystal structure 1. Introduction Methylation of histone lysine residues modulates gene expression, activating or inactivating it depending on the lysine site and degree of methylation [1]. Lysine-specific demethylase 1 (LSD1, also known as KDM1A) was the first histone demethylase to be reported, and its discovery proved that histone lysine methylation is a dynamic process regulated by methyltransferases and demethylases [2]. The biochemical properties and biological roles of LSD1 have been extensively investigated. LSD1 demethylates mono- and dimethylated Lys4 of histone H3 (H3Lys4), using flavin adenine dinucleotide (FAD) as a coenzyme [3]. The enzyme also demethylates H3Lys9 when bound to other proteins (e.g., the androgen receptor) or when expressed in its shortest isoform [4–6]. The catalytic domain is similar in its amino acid sequence and 3D structure to lysine-specific demethylase 2 (LSD2, also known as KDM1B) and other families of FAD-dependent enzymes, such as monoamine oxidases (MAOs) and polyamine oxidases (PAOs). However, LSD1 is unique in that its catalytic domain contains an elongated Tower domain where the REST corepressor 1 protein (CoREST) binds and presumably mediates LSD1 binding to a nucleosome (reviewed in [7]). LSD1 is highly expressed in several cancers and is involved in maintaining the stem cell properties of cancer cells, such as Molecules 2018, 23, 1538; doi:10.3390/molecules23071538 www.mdpi.com/journal/molecules Molecules 2018, 23, 1538 2 of 9 Molecules 2018, 23, x FOR PEER REVIEW 2 of 9 involvedthose involved in acute in acute myeloid myeloid leukemia leukemia (AML) (AML) and and glioblastoma glioblastoma [8–10]. [8–10]. Ther Therefore,efore, LSD1-selective inhibitors are expected toto serveserve asas therapeutictherapeutic agents forfor thesethese diseases.diseases. In the earlyearly stagesstages ofof thethe developmentdevelopment ofof LSD1LSD1 inhibitors,inhibitors, transtrans-2-phenylcyclopropylamine-2-phenylcyclopropylamine (2-PCPA, or or tranylcypromine), tranylcypromine), a aMAO MAO inhibitor, inhibitor, was was used used as a asmolecular a molecular scaffold. scaffold. Compounds Compounds based onbased this on scaffold this scaffold are irreversible are irreversible inhibitors inhibitors that covalently that covalently bind to bind FAD. to FAD.Information Information obtained obtained from crystalfrom crystal structures structures of LSD1 of LSD1 or the or theLSD1•CoREST LSD1•CoREST complex, complex, bound bound to to 2-PCPA 2-PCPA and and its its derivatives (review [[7])7]) hashas beenbeen used used to to develop develop potent potent and and selective selective inhibitors inhibitors of LSD1of LSD1 [11 [11,12],,12], some some of which of which are arecurrently currently being being tested tested in early-phase in early-phase clinical trialsclinical [7, 13trials]. In contrast,[7,13]. In progress contrast, toward progress the development toward the developmentof reversible small-molecule of reversible small-mol inhibitorsecule that inhibitors noncovalently that noncovalently bind to LSD1 hasbind been to LSD1 slow, has and been inhibitory slow, potenciesand inhibitory have potencies remained have in the remained micromolar in the range, micromolar possibly range, because possibly finding because a small finding molecule a small that moleculebinds strongly that binds to the strongly spacious to cavitythe spacious of LSD1, cavity which of LSD1, accommodates which accommodates the histone H3 the N-terminal histone H3 tailN- peptide,terminal istail difficult. peptide, However, is difficult. several However, kinds several of reversible kinds of inhibitors reversible with inhibitors submicromolar with submicromolar inhibitory potencyinhibitory have potency recently have been recently reported been [reported7,14]. Development [7,14]. Development of reversible of reversible LSD1 inhibitors LSD1 inhibitors may be maybeneficial be beneficial in drug development in drug development to avoid potential to avoid risks potential that irreversible risks that inhibitors irreversible would inhibitors cause through would causereactive through metabolites, reactive such metabolites, as an immune such as response an immune to the response adducted to proteinthe adducted and an protein unpredictable and an unpredictableidiosyncratic toxicity. idiosyncratic toxicity. Although many researchers working on the developmentdevelopment of reversible LSD1 inhibitors have performed in silico docking experiments, studie studiess involving structural methods such as X-ray crystallography areare limited limited in in number. number. Mattevi Mattevi and Maiand etMai al. haveet al. demonstrated have demonstrated that LSD1 that is inhibitedLSD1 is inhibitedby the antibiotics by the polymyxinsantibiotics polymyxins B and E, as wellB and as theE, histoneas wellmethyltransferase as the histone methyltransferase G9a inhibitor E11 G9a [15]. Theinhibitor crystal E11 structures [15]. The crystal of LSD1 structures•CoREST of bound LSD1•CoREST to these compounds bound to these indicate compounds that the indicate polymyxin that themolecules polymyxin bind molecules to the negatively bind to charged the negatively entrance char of theged substrate-binding entrance of the substrate-binding cavity of LSD1 in cavity multiple of LSD1rotated in orientations multiple rotated [15]. E11 orientations also binds to[15]. the E11 cavity also entrance, binds butto the in acavity stack consistingentrance, ofbut five in toa sevenstack consistingmolecules ofof the five inhibitor. to seven Recently, molecules Vianello of the and inhibitor. Sartori et Recently, al. [16,17 ]Vianello determined and the Sartori crystal et structure al. [16,17] of determinedLSD1•CoREST the incrystal complex structure with a of reversible LSD1•CoREST inhibitor in that complex was selected with aby reversible high-throughput inhibitor screeningthat was selectedof a chemical by high-throughput library. On the screening basis of the of structure,a chemical these library. investigators On the basis developed of the reversiblestructure, LSD1these investigatorsinhibitors with developed single-digit reversible nanomolar LSD1 IC inhibitors50 values [with17]. Thesingle-digit binding nanomolar modes of the IC50 newly values developed [17]. The bindinginhibitors modes were of validated the newly on developed the basis ofinhibitors crystal structureswere validated of their on complexesthe basis of with crystal LSD1 structures•CoREST. of theirFinally, complexes the crystal with structure LSD1•CoREST. of LSD1•CoREST Finally, with the noncovalently crystal structure bound tetrahydrofolateof LSD1•CoREST has beenwith noncovalentlyreported, although bound tetrahydrofolate tetrahydrofolate had has no been effect report on theed, activityalthough of tetrahydrofolate LSD1 in an in vitro hadbiochemical no effect on theassay activity [18]. of LSD1 in an in vitro biochemical assay [18]. In this paper, we present the crystal crystal structure structure of of LSD1•CoREST LSD1•CoREST in complex complex with with 4-[5-(piperidin- 4-[5-(piperidin- 4-ylmethoxy)-2-(pp-tolyl)pyridin-3-yl]benzonitrile-tolyl)pyridin-3-yl]benzonitrile ( (11, ,Figure Figure 11),), whichwhich waswas recentlyrecently reportedreported toto bebe aa reversible LSD1 inhibitor with a Ki of 29 nM [19]. [19]. The crystal stru structurecture presented here demonstrates that 1 bindsbinds inin aa novelnovel mode mode that that was was not not fully fully predicted
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