Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

Mould, Daniel P.; Alli, Cristina; Bremberg, Ulf; Cartic, Sharon; Jordan, Allan M.; Geitmann, Matthis; Maiques-Díaz, Alba; McGonagle, Alison E.; Somervaille, Tim C. P.; Spencer, Gary J.; Turlais, Fabrice; Ogilvie, Donald

doi:10.1021/acs.jmedchem.7b00462

Cited by 39 publications

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“…To determine whether this mechanism was generally applicable to other, structurally unrelated LSD1 inhibitors that also target the substrate interaction and catalytic site of LSD1, we repeated experiments using three different reversible inhibitors: (R)-4-(5-(pyrrolidin-3-ylmethoxy)-2-(p-tolyl)pyridin-3-yl) benzonitrile) (GSK354; Hitchin et al., 2013 ); 4-[3-[(3R)-3-aminopiperidine-1-carbonyl]-5-[(3-ethylisoxazol-5-yl)methoxy]pyrazol-1-yl] benzonitrile (Compound 11p; PDD31777; Mould et al., 2017a ); and 4-[[2-(2,7-Diazaspiro[3.5]nonan-7-yl)-2-oxo-ethyl]-[(3-fluoro-4-methoxy-phenyl)methyl]amino] benzonitrile (Compound 32; PDD32116; Mould et al., 2017b ) ( Figure S4 E). In each case, we found that drug-induced upregulation of the differentiation-linked cell-surface marker CD86 could be prevented by expression of the GFI1 ZNF-LSD1 fusion ( Figure 4 E) and that the interaction of GFI with LSD1 was impaired ( Figure 4 F; data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

et al. 2018

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SummaryPharmacologic inhibition of LSD1 promotes blast cell differentiation in acute myeloid leukemia (AML) with MLL translocations. The assumption has been that differentiation is induced through blockade of LSD1’s histone demethylase activity. However, we observed that rapid, extensive, drug-induced changes in transcription occurred without genome-wide accumulation of the histone modifications targeted for demethylation by LSD1 at sites of LSD1 binding and that a demethylase-defective mutant rescued LSD1 knockdown AML cells as efficiently as wild-type protein. Rather, LSD1 inhibitors disrupt the interaction of LSD1 and RCOR1 with the SNAG-domain transcription repressor GFI1, which is bound to a discrete set of enhancers located close to transcription factor genes that regulate myeloid differentiation. Physical separation of LSD1/RCOR1 from GFI1 is required for drug-induced differentiation. The consequent inactivation of GFI1 leads to increased enhancer histone acetylation within hours, which directly correlates with the upregulation of nearby subordinate genes.

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Section: Resultsmentioning

confidence: 99%

“…OG86, GSK354, PDD31777, and PDD32116 were synthesized in house, as described previously ( Harris et al., 2012 , Hitchin et al., 2013 , Mould et al., 2017a , Mould et al., 2017b ). Details of other reagents, antibodies, and biochemical methods are given in the Supplemental Information .…”

Section: Methodsmentioning

confidence: 99%

Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

et al. 2018

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“…NCD38, a tranylcypromine-based LSD1 inhibitor that impairs growth of the MLL-AF9-positive leukemia cell model MOLM14, reduces HOXA9 expression and induces myeloid differentiation [192]. JL1037, selected by computational screening, evidenced G0/G1 cell arrest in the THP-1 cell model (MLL-AF9) [193] or the 4-cyanophenyl-glycine derivative 32 active at the nanomolar range on LSD1 as evidenced by surface plasmon resonance [194].…”

Section: Indirect Targeting Of Hoxa9 At the Expression Levelmentioning

confidence: 99%

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia.

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Alioui

Jambon

et al. 2019

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HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an “undruggable” target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.

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“…Because of this similarity, the binding mode of GSK-690 is expected to be the same as that of compound 1 presented in this study. A crystal structure of GSK-690 bound to LSD1 is referred to in one report [ 22 ], but to our knowledge, structural data for the LSD1•GSK-690 complex are not available in the public domain.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1

Cited by 39 publications

References 33 publications

Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia.

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

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