Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family

Camilo E. Quevedo; Carole J. R. Bataille; Simon Byrne; Matthew Durbin; Jon Elkins; Abigail Guillermo; Alan M. Jones; Stefan Knapp; Anna Nadali; Roderick G. Walker; Isabel Wilkinson; Graham M. Wynne; Stephen G. Davies; Angela J. Russell

doi:10.1016/j.bmc.2020.115724

Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family

Camilo E. Quevedo, Carole J. R. Bataille, Simon Byrne, Matthew Durbin, Jon Elkins, Abigail Guillermo, Alan M. Jones, Stefan Knapp, Anna Nadali, Roderick G. Walker, Isabel Wilkinson, Graham M. Wynne, Stephen G. Davies, Angela J. Russell

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Abstract

We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.

Original language	English
Article number	115724
Journal	Bioorganic & Medicinal Chemistry
Volume	28
Issue number	22
DOIs	https://doi.org/10.1016/j.bmc.2020.115724
Publication status	Published - 15 Nov 2020

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Quevedo, C. E., J. R. Bataille, C., Byrne, S., Durbin, M., Elkins, J., Guillermo, A., Jones, A. M., Knapp, S., Nadali, A., Walker, R. G., Wilkinson, I., Wynne, G. M., Davies, S. G., & Russell, A. J. (2020). Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family. Bioorganic & Medicinal Chemistry, 28(22), Article 115724. https://doi.org/10.1016/j.bmc.2020.115724

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title = "Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family",

abstract = "We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.",

author = "Quevedo, {Camilo E.} and {J. R. Bataille}, Carole and Simon Byrne and Matthew Durbin and Jon Elkins and Abigail Guillermo and Jones, {Alan M.} and Stefan Knapp and Anna Nadali and Walker, {Roderick G.} and Isabel Wilkinson and Wynne, {Graham M.} and Davies, {Stephen G.} and Russell, {Angela J.}",

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Quevedo, CE, J. R. Bataille, C, Byrne, S, Durbin, M, Elkins, J, Guillermo, A, Jones, AM, Knapp, S, Nadali, A, Walker, RG, Wilkinson, I, Wynne, GM, Davies, SG & Russell, AJ 2020, 'Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family', Bioorganic & Medicinal Chemistry, vol. 28, no. 22, 115724. https://doi.org/10.1016/j.bmc.2020.115724

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T1 - Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family

AU - Quevedo, Camilo E.

AU - J. R. Bataille, Carole

AU - Byrne, Simon

AU - Durbin, Matthew

AU - Elkins, Jon

AU - Guillermo, Abigail

AU - Jones, Alan M.

AU - Knapp, Stefan

AU - Nadali, Anna

AU - Walker, Roderick G.

AU - Wilkinson, Isabel

AU - Wynne, Graham M.

AU - Davies, Stephen G.

AU - Russell, Angela J.

PY - 2020/11/15

Y1 - 2020/11/15

N2 - We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.

AB - We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.

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DO - 10.1016/j.bmc.2020.115724

M3 - Article

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VL - 28

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

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M1 - 115724

ER -

Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family

Abstract

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