The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode

Stephen T. Wrobleski; Shuqun Lin; T. G. Murali Dhar; Alaric J. Dyckman; Tianle Li; Sidney Pitt; Rosemary Zhang; Yi Fan; Arthur M. Doweyko; John S. Tokarski; Kevin F. Kish; Susan E. Kiefer; John S. Sack; John A. Newitt; Mark R. Witmer; Murray McKinnon; Joel C. Barrish; John H. Dodd; Gary L. Schieven; Katerina Leftheris

doi:10.1016/j.bmcl.2013.05.047

The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode

Stephen T. Wrobleski
, Shuqun Lin
, T. G. Murali Dhar
, Alaric J. Dyckman
, Tianle Li
, Sidney Pitt
, Rosemary Zhang
, Yi Fan
, Arthur M. Doweyko
, John S. Tokarski
, Kevin F. Kish
, Susan E. Kiefer
, John S. Sack
, John A. Newitt
, Mark R. Witmer
, Murray McKinnon
, Joel C. Barrish
, John H. Dodd
, Gary L. Schieven
, Katerina Leftheris

Chemistry

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

16 Scopus citations

Abstract

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.

Original language	English (US)
Pages (from-to)	4120-4126
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2013.05.047
State	Published - Jul 15 2013

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmcl.2013.05.047

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Wrobleski, S. T., Lin, S., Murali Dhar, T. G., Dyckman, A. J., Li, T., Pitt, S., Zhang, R., Fan, Y., Doweyko, A. M., Tokarski, J. S., Kish, K. F., Kiefer, S. E., Sack, J. S., Newitt, J. A., Witmer, M. R., McKinnon, M., Barrish, J. C., Dodd, J. H., Schieven, G. L., & Leftheris, K. (2013). The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode. Bioorganic and Medicinal Chemistry Letters, 23(14), 4120-4126. https://doi.org/10.1016/j.bmcl.2013.05.047

@article{6cfdbd68e0a74386a9432822b0d26ead,

title = "The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode",

abstract = "A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.",

author = "Wrobleski, \{Stephen T.\} and Shuqun Lin and \{Murali Dhar\}, \{T. G.\} and Dyckman, \{Alaric J.\} and Tianle Li and Sidney Pitt and Rosemary Zhang and Yi Fan and Doweyko, \{Arthur M.\} and Tokarski, \{John S.\} and Kish, \{Kevin F.\} and Kiefer, \{Susan E.\} and Sack, \{John S.\} and Newitt, \{John A.\} and Witmer, \{Mark R.\} and Murray McKinnon and Barrish, \{Joel C.\} and Dodd, \{John H.\} and Schieven, \{Gary L.\} and Katerina Leftheris",

year = "2013",

month = jul,

day = "15",

doi = "10.1016/j.bmcl.2013.05.047",

language = "English (US)",

volume = "23",

pages = "4120--4126",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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Wrobleski, ST, Lin, S, Murali Dhar, TG, Dyckman, AJ, Li, T, Pitt, S, Zhang, R, Fan, Y, Doweyko, AM, Tokarski, JS, Kish, KF, Kiefer, SE, Sack, JS, Newitt, JA, Witmer, MR, McKinnon, M, Barrish, JC, Dodd, JH, Schieven, GL & Leftheris, K 2013, 'The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 14, pp. 4120-4126. https://doi.org/10.1016/j.bmcl.2013.05.047

TY - JOUR

T1 - The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode

AU - Wrobleski, Stephen T.

AU - Lin, Shuqun

AU - Murali Dhar, T. G.

AU - Dyckman, Alaric J.

AU - Li, Tianle

AU - Pitt, Sidney

AU - Zhang, Rosemary

AU - Fan, Yi

AU - Doweyko, Arthur M.

AU - Tokarski, John S.

AU - Kish, Kevin F.

AU - Kiefer, Susan E.

AU - Sack, John S.

AU - Newitt, John A.

AU - Witmer, Mark R.

AU - McKinnon, Murray

AU - Barrish, Joel C.

AU - Dodd, John H.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2013/7/15

Y1 - 2013/7/15

N2 - A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.

AB - A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.

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UR - https://www.scopus.com/pages/publications/84879420782#tab=citedBy

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 14

ER -

The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode

Abstract

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