Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1

Daniel P. Mould; Ulf Bremberg; Allan M. Jordan; Matthis Geitmann; Alba Maiques-Diaz; Alison E. McGonagle; Helen F. Small; Tim C.P. Somervaille; Donald Ogilvie

doi:10.1016/j.bmcl.2017.05.018

Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1

Daniel P. Mould, Ulf Bremberg, Allan M. Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E. McGonagle, Helen F. Small, Tim C.P. Somervaille, Donald Ogilvie

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Abstract

A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC₅₀ value of 0.23 µM. Optimisation of this compound by rational design afforded compounds with K_d values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound.

Original language	English
Pages (from-to)	3190-3195
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	27
Issue number	14
Early online date	8 May 2017
DOIs	https://doi.org/10.1016/j.bmcl.2017.05.018
Publication status	Published - 15 Jul 2017

Keywords

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

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.2017.05.018

BMCL Submission Revision Tracked ChangesAccepted author manuscript, 1.64 MB

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Mould, D. P., Bremberg, U., Jordan, A. M., Geitmann, M., Maiques-Diaz, A., McGonagle, A. E., Small, H. F., Somervaille, T. C. P., & Ogilvie, D. (2017). Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1. Bioorganic and Medicinal Chemistry Letters, 27(14), 3190-3195. Advance online publication. https://doi.org/10.1016/j.bmcl.2017.05.018

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abstract = "A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23 µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound.",

keywords = "Acute myeloid leukaemia, Cancer therapy, Epigenetic therapy, Epigenetics, KDM1A, LSD1, Reversible inhibitor, Stem cell differentiation",

author = "Mould, {Daniel P.} and Ulf Bremberg and Jordan, {Allan M.} and Matthis Geitmann and Alba Maiques-Diaz and McGonagle, {Alison E.} and Small, {Helen F.} and Somervaille, {Tim C.P.} and Donald Ogilvie",

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T1 - Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1

AU - Mould, Daniel P.

AU - Bremberg, Ulf

AU - Jordan, Allan M.

AU - Geitmann, Matthis

AU - Maiques-Diaz, Alba

AU - McGonagle, Alison E.

AU - Small, Helen F.

AU - Somervaille, Tim C.P.

AU - Ogilvie, Donald

PY - 2017/7/15

Y1 - 2017/7/15

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AB - A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23 µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound.

KW - Acute myeloid leukaemia

KW - Cancer therapy

KW - Epigenetic therapy

KW - Epigenetics

KW - KDM1A

KW - LSD1

KW - Reversible inhibitor

KW - Stem cell differentiation

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M3 - Article

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SN - 0960-894X

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EP - 3195

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 14

ER -

Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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