Stafiba: A STAT5-Selective Small-Molecule Inhibitor

Abstract

The transcription factors STAT5a and STAT5b are constitutively active in many human tumors. Combined inhibition of both STAT5 proteins is a valuable approach with promising applications in tumor biology. We recently reported resorcinol bisphosphate as a moderately active inhibitor of the protein-protein interaction domains, the SH2 domains, of both STAT5a and STAT5b. Here, we describe the development of resorcinol bisphosphate to Stafiba, a phosphatase-stable inhibitor of STAT5a and STAT5b with activity in the low micromolar concentration range. Our data provide insights into the structure-activity relationships of resorcinol bisphosphates and the corresponding bisphosphonates for use as inhibitors of both STAT5a and STAT5b.

Keywords: SH2 domains; biological activity; inhibitors; protein-protein interactions; transcription factors.

Figure 1

Structures of A) catechol bisphosphate and Stafib‐2, and B) resorcinol bisphosphate (1). C) Binding mode of 1 to STAT5b as suggested by AutoDockFR. The Figure was created using PyMOL.

Figure 2

A) Synthesis of the building block 5 e and B) its use in the synthesis of 5.

Figure 3

Activity of 5 in fluorescence polarization assays.

Figure 4

Synthesis of 10.

Figure 5

A) Activity of 10 in fluorescence polarization assays against STAT proteins. B) Binding mode of 10 suggested by docking with AutoDockFR. The Figure was created using PyMOL. C) Activity of 10 and AC‐4‐130 against STAT5a and STAT5b in FP assays.