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Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a

Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a
Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a
Src homology 2 (SH2) domains play a central role in signal transduction. Although many SH2 domains have been validated as drug targets, their structural similarity makes development of specific inhibitors difficult. The cancer‐relevant transcription factors STAT5a and STAT5b are particularly challenging small‐molecule targets because their SH2 domains are 93 % identical on the amino acid level. Here we present the natural product‐inspired development of the low‐nanomolar inhibitor Stafib‐1, as the first small molecule which inhibits the STAT5b SH2 domain (Ki=44 nM) with more than 50‐fold selectivity over STAT5a. The binding site of the core moiety of Stafib‐1 was validated by functional analysis of point mutants. A prodrug of Stafib‐1 was shown to inhibit STAT5b with high selectivity over STAT5a in tumor cells. Stafib‐1 provides the first demonstration that naturally occurring SH2 domains with more than 90 % sequence identity can be selectively targeted with small organic molecules.
1433-7851
4758-4763
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Berg, Angela
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Natarajan, Kalaiselvi
dbdd2bb9-fb55-4274-b748-33c14d08e437
Scharow, Andrej
b537dc76-68df-4e5a-aa59-82d55236e7aa
Berg, Thorsten
c71a08bf-0b51-4550-b9c3-6cb4367cb828
Elumalai, Nagarajan
906d0161-3780-4778-ba5e-86ce313faf8d
Berg, Angela
640a620e-f724-4510-99f3-a906921cb11f
Natarajan, Kalaiselvi
dbdd2bb9-fb55-4274-b748-33c14d08e437
Scharow, Andrej
b537dc76-68df-4e5a-aa59-82d55236e7aa
Berg, Thorsten
c71a08bf-0b51-4550-b9c3-6cb4367cb828

Elumalai, Nagarajan, Berg, Angela, Natarajan, Kalaiselvi, Scharow, Andrej and Berg, Thorsten (2015) Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a. Angewandte Chemie International Edition, 54 (16), 4758-4763. (doi:10.1002/anie.201410672).

Record type: Article

Abstract

Src homology 2 (SH2) domains play a central role in signal transduction. Although many SH2 domains have been validated as drug targets, their structural similarity makes development of specific inhibitors difficult. The cancer‐relevant transcription factors STAT5a and STAT5b are particularly challenging small‐molecule targets because their SH2 domains are 93 % identical on the amino acid level. Here we present the natural product‐inspired development of the low‐nanomolar inhibitor Stafib‐1, as the first small molecule which inhibits the STAT5b SH2 domain (Ki=44 nM) with more than 50‐fold selectivity over STAT5a. The binding site of the core moiety of Stafib‐1 was validated by functional analysis of point mutants. A prodrug of Stafib‐1 was shown to inhibit STAT5b with high selectivity over STAT5a in tumor cells. Stafib‐1 provides the first demonstration that naturally occurring SH2 domains with more than 90 % sequence identity can be selectively targeted with small organic molecules.

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Elumalai et al 2015 Angewandte Chemie International Edition - Version of Record
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e-pub ahead of print date: 20 February 2015

Identifiers

Local EPrints ID: 428157
URI: https://eprints.soton.ac.uk/id/eprint/428157
ISSN: 1433-7851
PURE UUID: 484476c9-13ad-4443-b5a2-76626c73110f
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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