A Small Molecule Compound Targeting STAT3 DNA-Binding Domain Inhibits Cancer Cell Proliferation, Migration, and Invasion

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. STAT3 is constitutively activated in many malignant tumors and its activation is associated with high histological grade and advanced cancer stages. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced and metastatic cancers. Herein, we identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding domain of STAT3 using an improved virtual screening strategy. InS3-54 preferentially suppresses proliferation of cancer over non-cancer cells and inhibits migration and invasion of malignant cells. Biochemical analyses show that inS3-54 selectively inhibits STAT3 binding to DNA without affecting the activation and dimerization of STAT3. Furthermore, inS3-54 inhibits expression of STAT3 downstream target genes and STAT3 binding to chromatin in situ. Thus, inS3-54 represents a novel probe for development of specific inhibitors targeting the DNA-binding domain of STAT3 and a potential therapeutic for cancer treatments.

Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity

“…41). Using excellent wet chemistry and computer-assisted methods, many compounds have been created that attack this target, several successfully, reducing tyrosine 705 phosphorylation, inhibiting tumor cells in culture, and even effecting a modest inhibition of human tumor xenografts in mice (20,(42)(43)(44)(45). However, no molecule has been devised or unearthed that has adequate specificity and pharmacologic efficacy to provide hope that this obvious anticancer target will soon yield an effective anti-STAT3 drug in humans.…”

Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors

“…Structure-based in silico screening was performed as previously described (30,31). Briefly, the three-dimensional coordinates of survivin were acquired from PDB code 1F3H.…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…To date, inhibition of STAT function has been attempted through several approaches, including N-terminal domain binders [131], oligonucleotides targeting the DNA binding domain [132], and most effectively through use of small molecule compounds that bind the SH 2 domain to block STAT phosphorylation, dimerization, nuclear transport, and target gene expression [133–135]. …”

“…The vast majority of medicinal chemistry efforts to target STAT proteins have been conducted to develop specific inhibitors against STAT3 [130–132,136–148], with fewer reports of inhibitory modulators of STAT5A/B. The FDA-approved neuroleptic agent Pimozide was identified in a high-throughput screen as an inhibitor of STAT5 phosphorylation and an inducer of apoptosis in CML cell lines [149].…”