Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

Christopher R. Coxon; Elizabeth Anscombe; Suzannah J. Harnor; Mathew P. Martin; Benoit Carbain; Bernard T. Golding; Ian R. Hardcastle; Lisa K. Harlow; Svitlana Korolchuk; Christopher J. Matheson; David R. Newell; Martin E. M. Noble; Mangaleswaran Sivaprakasam; Susan J. Tudhope; David M. Turner; Lan Z. Wang; Stephen R. Wedge; Christopher Wong; Roger J. Griffin; Jane A. Endicott; Céline Cano

doi:10.1021/acs.jmedchem.6b01254

Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

Christopher R. Coxon, Elizabeth Anscombe, Suzannah J. Harnor, Mathew P. Martin, Benoit Carbain, Bernard T. Golding, Ian R. Hardcastle, Lisa K. Harlow, Svitlana Korolchuk, Christopher J. Matheson, David R. Newell, Martin E. M. Noble, Mangaleswaran Sivaprakasam, Susan J. Tudhope, David M. Turner, Lan Z. Wang, Stephen R. Wedge, Christopher Wong, Roger J. Griffin, Jane A. Endicott^*Céline Cano

^*Corresponding author for this work

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

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Abstract

Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC₅₀ 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC₅₀ 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.

Original language	English
Pages (from-to)	1746-1767
Number of pages	22
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	5
Early online date	14 Feb 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01254
Publication status	Published - 9 Mar 2017

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Coxon, C. R., Anscombe, E., Harnor, S. J., Martin, M. P., Carbain, B., Golding, B. T., Hardcastle, I. R., Harlow, L. K., Korolchuk, S., Matheson, C. J., Newell, D. R., Noble, M. E. M., Sivaprakasam, M., Tudhope, S. J., Turner, D. M., Wang, L. Z., Wedge, S. R., Wong, C., Griffin, R. J., ... Cano, C. (2017). Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines. Journal of Medicinal Chemistry, 60(5), 1746-1767. https://doi.org/10.1021/acs.jmedchem.6b01254

@article{fd120f34930c4305b9e702b17d625042,

title = "Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines",

abstract = "Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.",

author = "Coxon, {Christopher R.} and Elizabeth Anscombe and Harnor, {Suzannah J.} and Martin, {Mathew P.} and Benoit Carbain and Golding, {Bernard T.} and Hardcastle, {Ian R.} and Harlow, {Lisa K.} and Svitlana Korolchuk and Matheson, {Christopher J.} and Newell, {David R.} and Noble, {Martin E. M.} and Mangaleswaran Sivaprakasam and Tudhope, {Susan J.} and Turner, {David M.} and Wang, {Lan Z.} and Wedge, {Stephen R.} and Christopher Wong and Griffin, {Roger J.} and Endicott, {Jane A.} and C{\'e}line Cano",

year = "2017",

month = mar,

day = "9",

doi = "10.1021/acs.jmedchem.6b01254",

language = "English",

volume = "60",

pages = "1746--1767",

journal = "Journal of Medicinal Chemistry",

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Coxon, CR, Anscombe, E, Harnor, SJ, Martin, MP, Carbain, B, Golding, BT, Hardcastle, IR, Harlow, LK, Korolchuk, S, Matheson, CJ, Newell, DR, Noble, MEM, Sivaprakasam, M, Tudhope, SJ, Turner, DM, Wang, LZ, Wedge, SR, Wong, C, Griffin, RJ, Endicott, JA & Cano, C 2017, 'Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines', Journal of Medicinal Chemistry, vol. 60, no. 5, pp. 1746-1767. https://doi.org/10.1021/acs.jmedchem.6b01254

Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines. / Coxon, Christopher R.; Anscombe, Elizabeth; Harnor, Suzannah J. et al.
In: Journal of Medicinal Chemistry, Vol. 60, No. 5, 09.03.2017, p. 1746-1767.

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

TY - JOUR

T1 - Cyclin-Dependent Kinase (CDK) Inhibitors

T2 - Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

AU - Coxon, Christopher R.

AU - Anscombe, Elizabeth

AU - Harnor, Suzannah J.

AU - Martin, Mathew P.

AU - Carbain, Benoit

AU - Golding, Bernard T.

AU - Hardcastle, Ian R.

AU - Harlow, Lisa K.

AU - Korolchuk, Svitlana

AU - Matheson, Christopher J.

AU - Newell, David R.

AU - Noble, Martin E. M.

AU - Sivaprakasam, Mangaleswaran

AU - Tudhope, Susan J.

AU - Turner, David M.

AU - Wang, Lan Z.

AU - Wedge, Stephen R.

AU - Wong, Christopher

AU - Griffin, Roger J.

AU - Endicott, Jane A.

AU - Cano, Céline

PY - 2017/3/9

Y1 - 2017/3/9

N2 - Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.

AB - Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.

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U2 - 10.1021/acs.jmedchem.6b01254

DO - 10.1021/acs.jmedchem.6b01254

M3 - Article

C2 - 28005359

AN - SCOPUS:85015068709

SN - 0022-2623

VL - 60

SP - 1746

EP - 1767

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

Abstract

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