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

Eric T. Larson, Kayode K. Ojo, Ryan C. Murphy, Steven 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

41 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Parasites
Phosphotransferases
Adenosine Triphosphate
Cryptosporidium parvum
Toxoplasma
Enzyme Inhibitors
Life Cycle Stages
Glycine
Health
calcium-dependent protein kinase

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1. / Larson, Eric T.; Ojo, Kayode K.; Murphy, Ryan C.; Johnson, Steven; Zhang, Zhongsheng; Kim, Jessica E.; Leibly, David J.; Fox, Anna M W; Reid, Molly C.; Dale, Edward J.; Perera, B. Gayani K; Kim, Jae; Hewitt, Stephen N.; Hol, Wim G J; Verlinde, Christophe L M J; Fan, Erkang; Van Voorhis, Wesley C.; Maly, Dustin J.; Merritt, Ethan A.

In: Journal of Medicinal Chemistry, Vol. 55, No. 6, 22.03.2012, p. 2803-2810.

Research output: Contribution to journalArticle

Larson, ET, Ojo, KK, Murphy, RC, Johnson, S, Zhang, Z, Kim, JE, Leibly, DJ, Fox, AMW, Reid, MC, Dale, EJ, Perera, BGK, Kim, J, Hewitt, SN, Hol, WGJ, Verlinde, CLMJ, Fan, E, Van Voorhis, WC, Maly, DJ & Merritt, EA 2012, 'Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1', Journal of Medicinal Chemistry, vol. 55, no. 6, pp. 2803-2810. https://doi.org/10.1021/jm201725v
Larson, Eric T. ; Ojo, Kayode K. ; Murphy, Ryan C. ; Johnson, Steven ; Zhang, Zhongsheng ; Kim, Jessica E. ; Leibly, David J. ; Fox, Anna M W ; Reid, Molly C. ; Dale, Edward J. ; Perera, B. Gayani K ; Kim, Jae ; Hewitt, Stephen N. ; Hol, Wim G J ; Verlinde, Christophe L M J ; Fan, Erkang ; Van Voorhis, Wesley C. ; Maly, Dustin J. ; Merritt, Ethan A. / Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 6. pp. 2803-2810.
@article{bed0971665544cbd83cf5f10cc0e2476,
title = "Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1",
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.",
author = "Larson, {Eric T.} and Ojo, {Kayode K.} and Murphy, {Ryan C.} and Steven Johnson and Zhongsheng Zhang and Kim, {Jessica E.} and Leibly, {David J.} and Fox, {Anna M W} and Reid, {Molly C.} and Dale, {Edward J.} and Perera, {B. Gayani K} and Jae Kim and Hewitt, {Stephen N.} and Hol, {Wim G J} and Verlinde, {Christophe L M J} and Erkang Fan and {Van Voorhis}, {Wesley C.} and Maly, {Dustin J.} and Merritt, {Ethan A.}",
year = "2012",
month = "3",
day = "22",
doi = "10.1021/jm201725v",
language = "English (US)",
volume = "55",
pages = "2803--2810",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1

AU - Larson, Eric T.

AU - Ojo, Kayode K.

AU - Murphy, Ryan C.

AU - Johnson, Steven

AU - Zhang, Zhongsheng

AU - Kim, Jessica E.

AU - Leibly, David J.

AU - Fox, Anna M W

AU - Reid, Molly C.

AU - Dale, Edward J.

AU - Perera, B. Gayani K

AU - Kim, Jae

AU - Hewitt, Stephen N.

AU - Hol, Wim G J

AU - Verlinde, Christophe L M J

AU - Fan, Erkang

AU - Van Voorhis, Wesley C.

AU - Maly, Dustin J.

AU - Merritt, Ethan A.

PY - 2012/3/22

Y1 - 2012/3/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863387278&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863387278&partnerID=8YFLogxK

U2 - 10.1021/jm201725v

DO - 10.1021/jm201725v

M3 - Article

C2 - 22369268

AN - SCOPUS:84863387278

VL - 55

SP - 2803

EP - 2810

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -