Discovery of SH-17 as a pioneering STAT3/HDAC bifunctional inhibitor that simultaneously impairs Tyr705 and Ser727 phosphorylation.

The concurrent inhibition of oncogenic STAT3 and HDAC is a feasible avenue to achieving synergism and delaying drug resistance. Tyr705 and Ser727 serve as the two phosphorylation sites critical for manipulating the biological function of STAT3. Despite their complementary role in tumorigenesis, STAT3/HDAC bifunctional inhibitors simultaneously blocking Tyr705 and Ser727 phosphorylation have not been documented. Herein, SH-17 has been identified as a pioneering STAT3/HDAC bifunctional inhibitor impairing STAT3 phosphorylation at both Tyr705 and Ser727. It exhibited submicromolar or low micromolar IC50 values (0.411-4.85 μM) against various STAT3-aberrant malignant cells. With a binding affinity of 0.87 μM to STAT3 in SPR assay, SH-17 also potently inhibited the biochemical activity of representative HDACs. In cancer cells, it dramatically impaired STAT3 phosphorylation at both Tyr705 and Ser727 and suppressed deacetylation of HDAC substrates at low micromolar concentration. SH-17 was capable of obstructing intracellular ATP production and mitochondrial OXPHOS. Besides, it induced cell cycle arrest at G0/G1 phase and apoptosis at submicromolar concentration. In addition to its in vitro performance, SH-17 demonstrated acceptable in vivo PK parameters following intraperitoneal administration, thereby deserving further optimization as a STAT3/HDAC bifunctional inhibitor.