The transcription factor STAT5A/B controls leukemic cell survival and disease progression. Especially, STAT5B as major STAT5 isoform driving BCR/ABL+ leukemia. Besides, STAT5B enables transformation by suppressing IFN-α/γ, thereby facilitating leukemogenesis. STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma. Stafib-1 acts as the first selective inhibitor of the STAT5b SH2 domain.

The most effective and selective approach by which to inhibit STAT proteins involves functional inhibition of the protein-protein interaction domain, the Src homology 2 (SH2) domain. In particular, the transcription factors STAT5a and STAT5b are highly homologous and are frequently referred to jointly as “STAT5”. These imply that they carry out identical functions. For example, both STAT5a and STAT5b constitutively activate in numerous human cancers, including human leukemias harboring the Philadelphia chromosome. In addition, the inhibition of STAT5b reduces tumor cell proliferation more than the inhibition of STAT5a.

In this study, researchers demonstrate STAT5b binding of catechol bisphosphate by solid-state nuclear magnetic resonance and report on rational optimization of Stafib-1 (Ki=44 nM) to Stafib-2 (Ki=9 nM). Using combined isothermal titration calorimetry (ITC) and protein point mutant analysis to validate the binding site of Stafib-2. The prodrug Pomstafib-2 selectively inhibits tyrosine phosphorylation of STAT5b in human leukemia cells and induces apoptosis in a STAT5-dependent manner. Particularly, Stafib-1 acts as a selective inhibitor of the STAT5b SH2 domain.

To summarise, Stafib-1 is a selective, nanomolar inhibitor of the transcription factor STAT5b. Moreover, Stafib-1 displays significantly increased activity whilst maintaining high selectivity over the closely related SH2 domain of STAT5a.

Nagarajan Elumalai,et al.Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b. Sci Rep.2017 Apr 11;7(1):819.