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PreprintCited by 2Protein 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 P., Fiedler, Dorothea·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.04.26.538378

Preprint — published as 10.7554/elife.88982 · Paper page

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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 towards the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by HDX-MS 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 wild-type 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
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-04-26
DOI
10.1101/2023.04.26.538378
OpenAlex
W4367325775
Cited by
2
References
2
Citations by year
2023: 2
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
Funders
  • Deutscher Akademischer Austauschdienst
  • Deutsche Forschungsgemeinschaft (390540038, TRR186/A08, TRR186, TRR186/ A08/ A24, EXC 2008)
  • Helmholtz-Zentrum Berlin für Materialien und Energie
  • Leibniz-Gemeinschaft
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 inhibition, gatekeeper mutation, high-throughput screening, hydrogen-deuterium exchange mass spectrometry, allosteric pocket, lead compound identification

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