Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Unfortunately, targeting STAT3 with small molecules has proven to be very challenging, and for full activation of STAT3, the cooperative phosphorylation of both tyrosine 705 (Tyr705) and serine 727 (Ser727) is needed. Further, a selective inhibitor of STAT3 dual phosphorylation has not been developed. Here, we identified a low nanomolar potency and highly selective small-molecule STAT3 inhibitor that simultaneously inhibits both STAT3 Tyr705 and Ser727 phosphorylation. YY002 potently inhibited STAT3-dependent tumor cell growth in vitro and achieved potent suppression of tumor growth and metastasis in vivo. More importantly, YY002 exhibited favorable pharmacokinetics, an acceptable safety profile, and superior antitumor efficacy compared to BBI608 (STAT3 inhibitor that has advanced into phase III trials). For the mechanism, YY002 is selectively bound to the STAT3 Src Homology 2 (SH2) domain over other STAT members, which strongly suppressed STAT3 nuclear and mitochondrial functions in STAT3-dependent cells. Collectively, this study suggests the potential of small-molecule STAT3 inhibitors as possible anticancer therapeutic agents.

WB518, a novel STAT3 inhibitor, effectively alleviates IMQ and TPA-induced animal psoriasis by inhibiting STAT3 phosphorylation and Keratin 17.

OBJECTIVES: Psoriasis is a prevalent chronic inflammatory skin disease in humans that is characterized by frequent relapses and challenging to cure. WB518 is a novel small molecule compound with an undisclosed structure. Therefore, our study aimed to investigate the therapeutic potential of WB518 in vitro and in vivo for the treatment of psoriasis, specifically targeting the abnormal proliferation, aberrant differentiation of epidermal keratinocytes, and pathogenic inflammatory response. MATERIALS AND METHODS: We employed dual luciferase reporter assay to screen compounds capable of inhibiting STAT3 gene transcription. Flow cytometry was utilized to analyze CD3-positive cells. Protein and mRNA levels were assessed through Western blotting, immunofluorescence, immunohistochemistry, and real-time PCR. Cell viability was measured using the MTS assay, while in vivo models of psoriasis induced by IMQ and TPA were employed to study the anti-psoriasis effect of WB518. RESULTS: WB518 was found to significantly reduce the mRNA and protein levels of Keratin 17 (K17) in HaCaT cells by inhibiting the phosphorylation of STAT3 Tyr705 (Y705). In the IMQ and TPA-induced psoriasis mouse model, WB518 effectively improved scaling, epidermal hyperplasia, and inflammation. WB518 also suppressed the expression of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, IL-17, and IL-23. Furthermore, WB518 decreased the proportion of CD3-positive cells in the psoriatic skin of mice. CONCLUSIONS: WB518 exhibits promising potential as a treatment candidate for psoriasis.

Selectively Targeting STAT3 Using a Small Molecule Inhibitor is a Potential Therapeutic Strategy for Pancreatic Cancer.

PURPOSE: Pancreatic cancer is the worst prognosis among all human cancers, and novel effective treatments are urgently needed. Signal transducer and activator of transcription 3 (STAT3) has been demonstrated as a promising target for pancreatic cancer. Meanwhile, selectively targeted STAT3 with small molecule remains been challenging. EXPERIMENTAL DESIGN: To specifically identify STAT3 inhibitors, more than 1.3 million compounds were screened by structure-based virtual screening and confirmed with the direct binding assay. The amino acid residues that WB436B bound to were verified by induced-fit molecular docking simulation, RosettaLigand computations, and site-directed mutagenesis. On-target effects of WB436B were examined by microscale thermophoresis, surface plasmon resonance, in vitro kinase assay, RNA sequencing, and selective cell growth inhibition assessment. In vivo studies were performed in four animal models to evaluate effects of WB436B on tumor growth and metastasis. Kaplan-Meier analyses were used to assess survival. RESULTS: WB436B selectively bound to STAT3 over other STAT families protein, and in vitro antitumor activities were improved by 10 to 1,000 fold than the representative STAT3 inhibitors. WB436B selectively inhibits STAT3-Tyr705 phosphorylation, STAT3 target gene expression, and the viability of STAT3-dependent pancreatic cancer cells. WB436B significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. Mechanistic studies showed that WB436B have unique binding sites located in STAT3 Src homology 2 domain. CONCLUSIONS: Our work presents the first-in-class selective STAT3 inhibitor WB436B as a potential therapeutic candidate for the treatment of pancreatic cancer.

Targeting STAT3 by a small molecule suppresses pancreatic cancer progression.

Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.

Diversity and population structure of a dominant deciduous tree based on morphological and genetic data.

Knowledge of the genetic diversity and structure of tree species across their geographic ranges is essential for sustainable use and management of forest ecosystems. Acer grosseri Pax., an economically and ecologically important maple species, is mainly distributed in North China. In this study, the genetic diversity and population differentiation of 24 natural populations of this species were evaluated using sequence-related amplified polymorphism markers and morphological characters. The results show that highly significant differences occurred in 32 morphological traits. The coefficient of variation of 34 characters was 18.19 %. Principal component analysis indicated that 18 of 34 traits explained 60.20 % of the total variance. The phenotypic differentiation coefficient (VST) was 36.06 % for all morphological traits. The Shannon-Wiener index of 34 morphological characters was 6.09, while at the population level, it was 1.77. The percentage of polymorphic bands of all studied A. grosseri populations was 82.14 %. Nei's gene diversity (He) and Shannon's information index (I) were 0.35 and 0.50, respectively. Less genetic differentiation was detected among the natural populations (GST = 0.20, ΦST = 0.10). Twenty-four populations of A. grosseri formed two main clusters, which is consistent with morphological cluster analysis. Principal coordinates analysis and STRUCTURE analysis supported the UPGMA-cluster dendrogram. There was no significant correlation between genetic and geographical distances among populations. Both molecular and morphological data suggested that A. grosseri is rich in genetic diversity. The high level of genetic variation within populations could be affected by the biological characters, mating system and lifespan of A. grosseri, whereas the lower genetic diversity among populations could be caused by effective gene exchange, selective pressure from environmental heterogeneity and the species' geographical range.