Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

Daniel Mould; Ulf Bremberg; Allan Jordan; Matthis Geitmann; Alison Mcgonagle; Timothy Somervaille; Gary Spencer; Donald Ogilvie

doi:10.1016/j.bmcl.2017.08.052

Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

Daniel Mould, Ulf Bremberg, Allan Jordan, Matthis Geitmann, Alison Mcgonagle, Timothy Somervaille, Gary Spencer, Donald Ogilvie

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Abstract

As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC₅₀ of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1.

Original language	English
Pages (from-to)	4755-4759
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	20
Early online date	24 Aug 2017
DOIs	https://doi.org/10.1016/j.bmcl.2017.08.052
Publication status	Published - 15 Oct 2017

Keywords

Epigenetics
LSD1
KDM1A
Reversible inhibitor
Stem cell differentiation
Cancer therapy
Epigenetic therapy
Acute myeloid leukaemia

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2017.08.052

BMCL.2017.08.52Accepted author manuscript, 1.15 MB

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title = "Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1",

abstract = "As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1.",

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T1 - Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

AU - Mould, Daniel

AU - Bremberg, Ulf

AU - Jordan, Allan

AU - Geitmann, Matthis

AU - Mcgonagle, Alison

AU - Somervaille, Timothy

AU - Spencer, Gary

AU - Ogilvie, Donald

PY - 2017/10/15

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AB - As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22 nM and a biochemical IC50 of 57 nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping as a method to develop structurally diverse, potent inhibitors of LSD1.

KW - Epigenetics

KW - LSD1

KW - KDM1A

KW - Reversible inhibitor

KW - Stem cell differentiation

KW - Cancer therapy

KW - Epigenetic therapy

KW - Acute myeloid leukaemia

U2 - 10.1016/j.bmcl.2017.08.052

DO - 10.1016/j.bmcl.2017.08.052

M3 - Article

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VL - 27

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EP - 4759

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 20

ER -

Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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