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

Research output: Contribution to journalArticle

9 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 languageEnglish (US)
Pages (from-to)4120-4126
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2013

All Science Journal Classification (ASJC) codes

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

Fingerprint Dive into the research topics of 'The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode'. Together they form a unique fingerprint.

  • Cite this

    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