Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

Theodore C. Jessop; James E. Tarver; Marianne Carlsen; Amy Xu; Jason P. Healy; Alexander Heim-Riether; Qinghong Fu; Jerry A. Taylor; David J. Augeri; Min Shen; Terry R. Stouch; Ronald V. Swanson; Leslie W. Tari; Michael Hunter; Isaac Hoffman; Philip E. Keyes; Xuan Chuan Yu; Maricar Miranda; Qingyun Liu; Jonathan C. Swaffield; S. David Kimball; Amr Nouraldeen; Alan G.E. Wilson; Ann Marie Di George Foushee; Kanchan Jhaver; Rick Finch; Steve Anderson; Tamas Oravecz; Kenneth G. Carson

doi:10.1016/j.bmcl.2009.09.081

Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

Theodore C. Jessop, James E. Tarver, Marianne Carlsen, Amy Xu, Jason P. Healy, Alexander Heim-Riether, Qinghong Fu, Jerry A. Taylor, David J. Augeri, Min Shen, Terry R. Stouch, Ronald V. Swanson, Leslie W. Tari, Michael Hunter, Isaac Hoffman, Philip E. Keyes, Xuan Chuan Yu, Maricar Miranda, Qingyun Liu, Jonathan C. SwaffieldS. David Kimball, Amr Nouraldeen, Alan G.E. Wilson, Ann Marie Di George Foushee, Kanchan Jhaver, Rick Finch, Steve Anderson, Tamas Oravecz, Kenneth G. Carson

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

7 Scopus citations

Abstract

A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.

Original language	English (US)
Pages (from-to)	6784-6787
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2009.09.081
State	Published - Dec 1 2009
Externally published	Yes

Keywords

Cancer
Deoxycytidine kinase
Immunology
Pharmacokinetics
Virology

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2009.09.081

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Jessop, T. C., Tarver, J. E., Carlsen, M., Xu, A., Healy, J. P., Heim-Riether, A., Fu, Q., Taylor, J. A., Augeri, D. J., Shen, M., Stouch, T. R., Swanson, R. V., Tari, L. W., Hunter, M., Hoffman, I., Keyes, P. E., Yu, X. C., Miranda, M., Liu, Q., ... Carson, K. G. (2009). Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 19(23), 6784-6787. https://doi.org/10.1016/j.bmcl.2009.09.081

Jessop, TC, Tarver, JE, Carlsen, M, Xu, A, Healy, JP, Heim-Riether, A, Fu, Q, Taylor, JA, Augeri, DJ, Shen, M, Stouch, TR, Swanson, RV, Tari, LW, Hunter, M, Hoffman, I, Keyes, PE, Yu, XC, Miranda, M, Liu, Q, Swaffield, JC, David Kimball, S, Nouraldeen, A, Wilson, AGE, Foushee, AMDG, Jhaver, K, Finch, R, Anderson, S, Oravecz, T & Carson, KG 2009, 'Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 23, pp. 6784-6787. https://doi.org/10.1016/j.bmcl.2009.09.081

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abstract = "A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.",

keywords = "Cancer, Deoxycytidine kinase, Immunology, Pharmacokinetics, Virology",

author = "Jessop, {Theodore C.} and Tarver, {James E.} and Marianne Carlsen and Amy Xu and Healy, {Jason P.} and Alexander Heim-Riether and Qinghong Fu and Taylor, {Jerry A.} and Augeri, {David J.} and Min Shen and Stouch, {Terry R.} and Swanson, {Ronald V.} and Tari, {Leslie W.} and Michael Hunter and Isaac Hoffman and Keyes, {Philip E.} and Yu, {Xuan Chuan} and Maricar Miranda and Qingyun Liu and Swaffield, {Jonathan C.} and {David Kimball}, S. and Amr Nouraldeen and Wilson, {Alan G.E.} and Foushee, {Ann Marie Di George} and Kanchan Jhaver and Rick Finch and Steve Anderson and Tamas Oravecz and Carson, {Kenneth G.}",

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doi = "10.1016/j.bmcl.2009.09.081",

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T1 - Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

AU - Jessop, Theodore C.

AU - Tarver, James E.

AU - Carlsen, Marianne

AU - Xu, Amy

AU - Healy, Jason P.

AU - Heim-Riether, Alexander

AU - Fu, Qinghong

AU - Taylor, Jerry A.

AU - Augeri, David J.

AU - Shen, Min

AU - Stouch, Terry R.

AU - Swanson, Ronald V.

AU - Tari, Leslie W.

AU - Hunter, Michael

AU - Hoffman, Isaac

AU - Keyes, Philip E.

AU - Yu, Xuan Chuan

AU - Miranda, Maricar

AU - Liu, Qingyun

AU - Swaffield, Jonathan C.

AU - David Kimball, S.

AU - Nouraldeen, Amr

AU - Wilson, Alan G.E.

AU - Foushee, Ann Marie Di George

AU - Jhaver, Kanchan

AU - Finch, Rick

AU - Anderson, Steve

AU - Oravecz, Tamas

AU - Carson, Kenneth G.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.

AB - A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.

KW - Cancer

KW - Deoxycytidine kinase

KW - Immunology

KW - Pharmacokinetics

KW - Virology

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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