Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

Carole J R Bataille; MB Brennan; S Byrne; SG Davies; M Durbin; O Federov; KVM Huber; Alan Jones; S Knapp; G Liu; A Nadali; CE Quevedo; AJ Russell; RG Walker; R Westwood; GM Wynne

doi:10.1016/j.bmc.2017.02.056

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

Carole J R Bataille, MB Brennan, S Byrne, SG Davies, M Durbin, O Federov, KVM Huber, Alan Jones, S Knapp, G Liu, A Nadali, CE Quevedo, AJ Russell, RG Walker, R Westwood, GM Wynne

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Abstract

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over
other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition

Original language	English
Pages (from-to)	2657-2665
Journal	Bioorganic & Medicinal Chemistry
Volume	25
Issue number	9
Early online date	28 Feb 2017
DOIs	https://doi.org/10.1016/j.bmc.2017.02.056
Publication status	Published - 1 May 2017

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Bataille_et_al_Thiazolidine_derivatives_Bioorganic_Medicinal_Chemistry
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Bataille, C. J. R., Brennan, MB., Byrne, S., Davies, SG., Durbin, M., Federov, O., Huber, KVM., Jones, A., Knapp, S., Liu, G., Nadali, A., Quevedo, CE., Russell, AJ., Walker, RG., Westwood, R., & Wynne, GM. (2017). Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family. Bioorganic & Medicinal Chemistry, 25(9), 2657-2665. Advance online publication. https://doi.org/10.1016/j.bmc.2017.02.056

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abstract = "The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity overother kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition",

author = "Bataille, {Carole J R} and MB Brennan and S Byrne and SG Davies and M Durbin and O Federov and KVM Huber and Alan Jones and S Knapp and G Liu and A Nadali and CE Quevedo and AJ Russell and RG Walker and R Westwood and GM Wynne",

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Bataille, CJR, Brennan, MB, Byrne, S, Davies, SG, Durbin, M, Federov, O, Huber, KVM, Jones, A, Knapp, S, Liu, G, Nadali, A, Quevedo, CE, Russell, AJ, Walker, RG, Westwood, R & Wynne, GM 2017, 'Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family', Bioorganic & Medicinal Chemistry, vol. 25, no. 9, pp. 2657-2665. https://doi.org/10.1016/j.bmc.2017.02.056

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T1 - Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

AU - Bataille, Carole J R

AU - Brennan, MB

AU - Byrne, S

AU - Davies, SG

AU - Durbin, M

AU - Federov, O

AU - Huber, KVM

AU - Jones, Alan

AU - Knapp, S

AU - Liu, G

AU - Nadali, A

AU - Quevedo, CE

AU - Russell, AJ

AU - Walker, RG

AU - Westwood, R

AU - Wynne, GM

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Y1 - 2017/5/1

N2 - The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity overother kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition

AB - The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity overother kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition

U2 - 10.1016/j.bmc.2017.02.056

DO - 10.1016/j.bmc.2017.02.056

M3 - Article

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VL - 25

SP - 2657

EP - 2665

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 9

ER -

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

Abstract

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