title: 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 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.
authors.affiliation: Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, 04103 Leipzig (Germany) http://www.uni-leipzig.de/∼tberg.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Elumalai
authors.forename: Angela
authors.initials: A
authors.lastname: Berg
authors.forename: Kalaiselvi
authors.initials: K
authors.lastname: Natarajan
authors.forename: Andrej
authors.initials: A
authors.lastname: Scharow
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism; D002396:Catechols / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D001688:Biological Products; D002396:Catechols; D010455:Peptides; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; C034221:catechol
keywords: STAT5; inhibitors; natural products; protein-protein interactions; transcription factors