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Phosphorylation of capsaicinoid derivatives provides highly potent and selective inhibitors of the transcription factor STAT5b

Phosphorylation of capsaicinoid derivatives provides highly potent and selective inhibitors of the transcription factor STAT5b
Phosphorylation of capsaicinoid derivatives provides highly potent and selective inhibitors of the transcription factor STAT5b
Design approaches for inhibitors of protein–protein interactions are rare, but highly sought after. Here, we report that O-phosphorylation of simple derivatives of the natural products dihydrocapsaicin and N-vanillylnonanamide leads to inhibitors of the SH2 domain of the transcription factor STAT5b. The most potent molecule is obtained from dihydrocapsaicin in only three synthetic steps. It has submicromolar affinity for the SH2 domain of STAT5b (Ki = 0.34 μM), while displaying 35-fold selectivity over the highly homologous STAT5a (Ki = 13.0 μM). The corresponding pivaloyloxymethyl ester inhibits STAT5b with selectivity over STAT5a in human tumor cells. Importantly, it inhibits cell viability and induces apoptosis in human tumor cells in a STAT5-dependent manner. Our data validate O-phosphorylation of appropriately preselected natural products or natural product derivatives as a semirational design approach for small molecules that selectively inhibit phosphorylation-dependent protein–protein interaction domains in cultured human tumor cells.
1554-8929
2884-2890
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Berg, Angela
e4feb090-7216-42bd-8941-66c9cc06909e
Rubner, Stefan
f22db49e-3bcd-405c-a0f0-de403835b052
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Berg, Angela
e4feb090-7216-42bd-8941-66c9cc06909e
Rubner, Stefan
f22db49e-3bcd-405c-a0f0-de403835b052

Elumalai, Nagarajan, Berg, Angela and Rubner, Stefan (2015) Phosphorylation of capsaicinoid derivatives provides highly potent and selective inhibitors of the transcription factor STAT5b. ACS Chemical Biology, 10 (12), 2884-2890. (doi:10.1021/acschembio.5b00817).

Record type: Article

Abstract

Design approaches for inhibitors of protein–protein interactions are rare, but highly sought after. Here, we report that O-phosphorylation of simple derivatives of the natural products dihydrocapsaicin and N-vanillylnonanamide leads to inhibitors of the SH2 domain of the transcription factor STAT5b. The most potent molecule is obtained from dihydrocapsaicin in only three synthetic steps. It has submicromolar affinity for the SH2 domain of STAT5b (Ki = 0.34 μM), while displaying 35-fold selectivity over the highly homologous STAT5a (Ki = 13.0 μM). The corresponding pivaloyloxymethyl ester inhibits STAT5b with selectivity over STAT5a in human tumor cells. Importantly, it inhibits cell viability and induces apoptosis in human tumor cells in a STAT5-dependent manner. Our data validate O-phosphorylation of appropriately preselected natural products or natural product derivatives as a semirational design approach for small molecules that selectively inhibit phosphorylation-dependent protein–protein interaction domains in cultured human tumor cells.

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e-pub ahead of print date: 15 October 2015

Identifiers

Local EPrints ID: 428156
URI: https://eprints.soton.ac.uk/id/eprint/428156
ISSN: 1554-8929
PURE UUID: 6240ee35-d21f-401d-bb22-270c88271f5c
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 Sep 2019 00:32

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