Nanomolar Inhibitors of the Transcription Factor STAT5b with High Selectivity over STAT5a

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 ( K i =44 n M ) 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.