Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

Shudong Wang; Carol A. Midgley; Frederic Scaërou; Joanna B. Grabarek; Gary Griffiths; Wayne Jackson; George Kontopidis; Steven J. McClue; Campbell McInnes; Christopher Meades; Mokdad Mezna; Andy Plater; Iain Stuart; Mark P. Thomas; Gavin Wood; Rosemary G. Clarke; David G. Blake; Daniella I. Zheleva; David P. Lane; Robert C. Jackson; David M. Glover; P.M. Fischer

doi:10.1021/jm901913s

Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

Shudong Wang, Carol A. Midgley, Frederic Scaërou, Joanna B. Grabarek, Gary Griffiths, Wayne Jackson, George Kontopidis, Steven J. McClue, Campbell McInnes, Christopher Meades, Mokdad Mezna, Andy Plater, Iain Stuart, Mark P. Thomas, Gavin Wood, Rosemary G. Clarke, David G. Blake, Daniella I. Zheleva, David P. Lane, Robert C. JacksonDavid M. Glover, P.M. Fischer

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Abstract

Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4- morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.

Original language	English
Pages (from-to)	4367-4378
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	11
Early online date	12 May 2010
DOIs	https://doi.org/10.1021/jm901913s
Publication status	Published - 10 Jun 2010

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Wang, S., Midgley, C. A., Scaërou, F., Grabarek, J. B., Griffiths, G., Jackson, W., Kontopidis, G., McClue, S. J., McInnes, C., Meades, C., Mezna, M., Plater, A., Stuart, I., Thomas, M. P., Wood, G., Clarke, R. G., Blake, D. G., Zheleva, D. I., Lane, D. P., ... Fischer, P. M. (2010). Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors. Journal of Medicinal Chemistry, 53(11), 4367-4378. https://doi.org/10.1021/jm901913s

@article{605c4e48f23c48f18da906242de4e58d,

title = "Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors",

abstract = "Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4- morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.",

author = "Shudong Wang and Midgley, {Carol A.} and Frederic Sca{\"e}rou and Grabarek, {Joanna B.} and Gary Griffiths and Wayne Jackson and George Kontopidis and McClue, {Steven J.} and Campbell McInnes and Christopher Meades and Mokdad Mezna and Andy Plater and Iain Stuart and Thomas, {Mark P.} and Gavin Wood and Clarke, {Rosemary G.} and Blake, {David G.} and Zheleva, {Daniella I.} and Lane, {David P.} and Jackson, {Robert C.} and Glover, {David M.} and P.M. Fischer",

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month = jun,

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Wang, S, Midgley, CA, Scaërou, F, Grabarek, JB, Griffiths, G, Jackson, W, Kontopidis, G, McClue, SJ, McInnes, C, Meades, C, Mezna, M, Plater, A, Stuart, I, Thomas, MP, Wood, G, Clarke, RG, Blake, DG, Zheleva, DI, Lane, DP, Jackson, RC, Glover, DM & Fischer, PM 2010, 'Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors', Journal of Medicinal Chemistry, vol. 53, no. 11, pp. 4367-4378. https://doi.org/10.1021/jm901913s

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T1 - Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

AU - Wang, Shudong

AU - Midgley, Carol A.

AU - Scaërou, Frederic

AU - Grabarek, Joanna B.

AU - Griffiths, Gary

AU - Jackson, Wayne

AU - Kontopidis, George

AU - McClue, Steven J.

AU - McInnes, Campbell

AU - Meades, Christopher

AU - Mezna, Mokdad

AU - Plater, Andy

AU - Stuart, Iain

AU - Thomas, Mark P.

AU - Wood, Gavin

AU - Clarke, Rosemary G.

AU - Blake, David G.

AU - Zheleva, Daniella I.

AU - Lane, David P.

AU - Jackson, Robert C.

AU - Glover, David M.

AU - Fischer, P.M.

N1 - MEDLINE® is the source for the MeSH terms of this document.

PY - 2010/6/10

Y1 - 2010/6/10

N2 - Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4- morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.

AB - Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4- morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.

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U2 - 10.1021/jm901913s

DO - 10.1021/jm901913s

M3 - Article

C2 - 20462263

AN - SCOPUS:77953221993

SN - 0022-2623

VL - 53

SP - 4367

EP - 4378

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

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