Discovery of a Natural Small-Molecule Inhibitor to Novel Target STAT5A for Ischemic Stroke Therapy

Signal transducer and activator of transcription 5A (STAT5A)
is
known to regulate the processes of various cancers but remains unexplored
in neuroprotective effects, especially in ischemic stroke (IS). Based
on an HPLC-DAD-HRESIMS-oriented strategy, 16 stilbenoid dimers [(+)-1/(−)-1 – (+)-9/(−)-9] were isolated from Heterosmilax yunnanensis (Liliaceae). Pharmacological evaluations showed that (±)-2 could remarkably alleviate neuronal ischemic damage in MCAO
models. A four-step synthesis of (±)-2 was achieved
in a stereo- and regioselective manner by a protecting-group-free
strategy. The SAR analysis indicated the necessity of two hydroxy
groups at C-3/C-4 or C-3/C-5 in the A ring. Using a chemoproteomics
technology, STAT5A was identified as the direct cellular target of
(±)-2. Mechanistically, (±)-2 conjugates
with STAT5A by the key Lys644 residue to inhibit its phosphorylation,
thus exerting anti-IS effects. Our findings demonstrate that STAT5A
might be a novel target for IS therapy, and (±)-2 was the first natural anti-IS drug candidate targeting STAT5A.