Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1

Eric T. Larson, Kayode K. Ojo, Ryan C. Murphy, Steven M. Johnson, Zhongsheng Zhang, Jessica E. Kim, David J. Leibly, Anna M.W. Fox, Molly C. Reid, Edward J. Dale, B. Gayani K. Perera, Jae Kim, Stephen N. Hewitt, Wim G.J. Hol, Christophe L.M.J. Verlinde, Erkang Fan, Wesley C. Van Voorhis, Dustin J. Maly, Ethan A. Merritt

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.

Original languageEnglish (US)
Pages (from-to)2803-2810
Number of pages8
JournalJournal of Medicinal Chemistry
Volume55
Issue number6
DOIs
StatePublished - Mar 22 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Larson, E. T., Ojo, K. K., Murphy, R. C., Johnson, S. M., Zhang, Z., Kim, J. E., Leibly, D. J., Fox, A. M. W., Reid, M. C., Dale, E. J., Perera, B. G. K., Kim, J., Hewitt, S. N., Hol, W. G. J., Verlinde, C. L. M. J., Fan, E., Van Voorhis, W. C., Maly, D. J., & Merritt, E. A. (2012). Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1. Journal of Medicinal Chemistry, 55(6), 2803-2810. https://doi.org/10.1021/jm201725v