Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells

Stuart Jones; Jonathan Ahmet; Kelly Ayton; Matthew Ball; Mark Cockerill; Emma Fairweather; Nicola Hamilton; Paul Harper; James Hitchin; Allan Jordan; Colin Levy; Ruth Lopez; Edward Mckenzie; Martin Packer; Darren Plant; Iain Simpson; Peter Simpson; Ian Sinclair; Tim C P Somervaille; Helen Small; Gary J Spencer; Graeme Thomson; Michael Tonge; Ian Waddell; Jarrod Walsh; Bohdan Waszkowycz; Mark Wigglesworth; Daniel H Wiseman; Donald Ogilvie

doi:10.1021/acs.jmedchem.6b01320

Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells

Stuart Jones, Jonathan Ahmet, Kelly Ayton, Matthew Ball, Mark Cockerill, Emma Fairweather, Nicola Hamilton, Paul Harper, James Hitchin, Allan Jordan, Colin Levy, Ruth Lopez, Edward Mckenzie, Martin Packer, Darren Plant, Iain Simpson, Peter Simpson, Ian Sinclair, Tim C P Somervaille, Helen SmallGary J Spencer, Graeme Thomson, Michael Tonge, Ian Waddell, Jarrod Walsh, Bohdan Waszkowycz, Mark Wigglesworth, Daniel H Wiseman, Donald Ogilvie

Research output: Contribution to journal › Article › peer-review

Abstract

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

Original language	English
Pages (from-to)	11120-11137
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	24
Early online date	15 Nov 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01320
Publication status	Published - 22 Dec 2016

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Manchester Institute of Biotechnology
Manchester Cancer Research Centre

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Jones, S., Ahmet, J., Ayton, K., Ball, M., Cockerill, M., Fairweather, E., Hamilton, N., Harper, P., Hitchin, J., Jordan, A., Levy, C., Lopez, R., Mckenzie, E., Packer, M., Plant, D., Simpson, I., Simpson, P., Sinclair, I., Somervaille, T. C. P., ... Ogilvie, D. (2016). Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells. Journal of Medicinal Chemistry, 59(24), 11120-11137. https://doi.org/10.1021/acs.jmedchem.6b01320

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title = "Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells",

abstract = "A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.",

author = "Stuart Jones and Jonathan Ahmet and Kelly Ayton and Matthew Ball and Mark Cockerill and Emma Fairweather and Nicola Hamilton and Paul Harper and James Hitchin and Allan Jordan and Colin Levy and Ruth Lopez and Edward Mckenzie and Martin Packer and Darren Plant and Iain Simpson and Peter Simpson and Ian Sinclair and Somervaille, {Tim C P} and Helen Small and Spencer, {Gary J} and Graeme Thomson and Michael Tonge and Ian Waddell and Jarrod Walsh and Bohdan Waszkowycz and Mark Wigglesworth and Wiseman, {Daniel H} and Donald Ogilvie",

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month = dec,

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doi = "10.1021/acs.jmedchem.6b01320",

language = "English",

volume = "59",

pages = "11120--11137",

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publisher = "American Chemical Society",

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Jones, S, Ahmet, J, Ayton, K, Ball, M, Cockerill, M, Fairweather, E, Hamilton, N, Harper, P, Hitchin, J, Jordan, A, Levy, C, Lopez, R, Mckenzie, E, Packer, M, Plant, D, Simpson, I, Simpson, P, Sinclair, I, Somervaille, TCP, Small, H, Spencer, GJ, Thomson, G, Tonge, M, Waddell, I, Walsh, J, Waszkowycz, B, Wigglesworth, M, Wiseman, DH & Ogilvie, D 2016, 'Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells', Journal of Medicinal Chemistry, vol. 59, no. 24, pp. 11120-11137. https://doi.org/10.1021/acs.jmedchem.6b01320

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T1 - Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells

AU - Jones, Stuart

AU - Ahmet, Jonathan

AU - Ayton, Kelly

AU - Ball, Matthew

AU - Cockerill, Mark

AU - Fairweather, Emma

AU - Hamilton, Nicola

AU - Harper, Paul

AU - Hitchin, James

AU - Jordan, Allan

AU - Levy, Colin

AU - Lopez, Ruth

AU - Mckenzie, Edward

AU - Packer, Martin

AU - Plant, Darren

AU - Simpson, Iain

AU - Simpson, Peter

AU - Sinclair, Ian

AU - Somervaille, Tim C P

AU - Small, Helen

AU - Spencer, Gary J

AU - Thomson, Graeme

AU - Tonge, Michael

AU - Waddell, Ian

AU - Walsh, Jarrod

AU - Waszkowycz, Bohdan

AU - Wigglesworth, Mark

AU - Wiseman, Daniel H

AU - Ogilvie, Donald

PY - 2016/12/22

Y1 - 2016/12/22

N2 - A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

AB - A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

U2 - 10.1021/acs.jmedchem.6b01320

DO - 10.1021/acs.jmedchem.6b01320

M3 - Article

C2 - 28002956

SN - 0022-2623

VL - 59

SP - 11120

EP - 11137

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells

Abstract

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