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Cited by 3Protein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancerBiochemical and Molecular Research

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An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor

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Aguirre, Tim, Dornan, Gillian L, Hostachy, Sarah, Neuenschwander, Martin, Seyffarth, Carola, Haucke, Volker, Schütz, Anja, von Kries, Jens Peter, Fiedler, Dorothea·2023·eLife
DOI 10.7554/elife.88982PMC PMC10578927

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Abstract

Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development of potent IP6K inhibitors is gaining momentum, a pharmacological tool to distinguish the mammalian isozymes is still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed a high-throughput screen to identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency and selectivity toward the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type (WT) kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by hydrogen deuterium exchange mass spectrometry measurements. The latter analysis suggested that displacement of the α C helix, caused by the gatekeeper mutation, facilitates the binding of FMP-201300 to an allosteric pocket adjacent to the ATP-binding site. FMP-201300 therefore serves as a valuable springboard for the further development of compounds that can selectively target the three mammalian IP6Ks; either as analog-sensitive kinase inhibitors or as an allosteric lead compound for the WT kinases.

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Metadata

Authors
Aguirre, T., Dornan, G. L., Hostachy, S., Neuenschwander, M., Seyffarth, C., Haucke, V., Schütz, A., von Kries, J. P., & Fiedler, D.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
  • Max Delbrück Center (DE)
Corresponding author
Fiedler, Dorothea
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2023-10-16
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.88982
PMC
PMC10578927
OpenAlex
W4381738355
Cited by
3
References
3
Citations by year
2026: 1 · 2025: 2
FWCI
0.27
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Deutsche Forschungsgemeinschaft (EXC 2008 - 390540038, TRR186/ A08/ A24)
  • German Academic Exchange Service (DAAD-Leibniz postdoctoral fellowship)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
inositol hexakisphosphate kinase, IP6K1, allosteric inhibitors, gatekeeper mutation, hydrogen-deuterium exchange mass spectrometry, lead compound identification
MeSH terms
Animals, Inositol Phosphates, Mammals, Phytic Acid, Phosphotransferases (Phosphate Group Acceptor)

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