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Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives

Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives
Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives
Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains.
1554-8929
1008-1014
Graeber, Martin
81ecbe70-0ef0-47fb-86a7-32d6229445a9
Janczyk, Weronika
a54fae85-f689-4fb6-9eda-1ffbb7bbce2d
Sperl, Bianca
bb855a2b-c4bb-403c-8c49-01355a1dd2c6
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Kozany, Christian
a4bb9726-6840-4ef7-adbe-dd4dbf9602b5
Hausch, Felix
a68fb951-c938-4300-a28a-77ce2f1f070a
Holak, Tad A
234157ba-1979-4125-be0e-55c150ec6711
Berg, Thorsten
d5459e2c-7da2-4bc2-9a11-8ec6b26b8d4b
Graeber, Martin
81ecbe70-0ef0-47fb-86a7-32d6229445a9
Janczyk, Weronika
a54fae85-f689-4fb6-9eda-1ffbb7bbce2d
Sperl, Bianca
bb855a2b-c4bb-403c-8c49-01355a1dd2c6
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Kozany, Christian
a4bb9726-6840-4ef7-adbe-dd4dbf9602b5
Hausch, Felix
a68fb951-c938-4300-a28a-77ce2f1f070a
Holak, Tad A
234157ba-1979-4125-be0e-55c150ec6711
Berg, Thorsten
d5459e2c-7da2-4bc2-9a11-8ec6b26b8d4b

Graeber, Martin, Janczyk, Weronika, Sperl, Bianca, Elumalai, Nagarajan, Kozany, Christian, Hausch, Felix, Holak, Tad A and Berg, Thorsten (2011) Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives. ACS Chemical Biology, 6 (10), 1008-1014. (doi:10.1021/cb2001796).

Record type: Article

Abstract

Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains.

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e-pub ahead of print date: 28 July 2011

Identifiers

Local EPrints ID: 428158
URI: https://eprints.soton.ac.uk/id/eprint/428158
ISSN: 1554-8929
PURE UUID: 975f20c3-844b-4a49-b323-ab9d076f5d4a
ORCID for Nagarajan Elumalai: ORCID iD orcid.org/0000-0001-7359-5218

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Date deposited: 13 Feb 2019 17:30
Last modified: 17 Jul 2019 00:32

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Contributors

Author: Martin Graeber
Author: Weronika Janczyk
Author: Bianca Sperl
Author: Christian Kozany
Author: Felix Hausch
Author: Tad A Holak
Author: Thorsten Berg

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