Design, synthesis and biological evaluation of novel diarylacylhydrazones derivatives for the efficient treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized with high mortality, unknown etiology, and lack of effective treatment. Many evidences validate that inhibiting the activation of STAT3 is an attractive therapeutic strategy for IPF. Herein, based on our previous findings that nifuroxazide (NIF) could effectively attenuate pulmonary fibrosis by inhibiting STAT3 activation, a series of diarylacylhydrazones derivatives have been designed and synthesized. Among them, compounds 44 and 52 could inhibit TGF-ß1-induced abnormal activation of NIH-3T3 and A549 cells, as well as migration and EMT of A549 cells. In a bleomycin-induced mouse pulmonary fibrosis model, the oral administration of 44 and 52 (bioavailability F = 31.75% and 42.08%) improved mouse lung function and slowed the progression of IPF. Moreover, 52 could reverse the pulmonary fibrosis in treatment model. Collectively, this work shows 44 and 52 could be a potential lead compound for the treatment of IPF, and it is worthy of further study.

Discovery of the novel Benzo[b]thiophene 1,1-dioxide derivatives as a potent STAT3 inhibitor against idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown aetiology with limited treatment options. Currently, only two drugs, nintedanib and pirfenidone, are approved for the clinical treatment of IPF, but their efficacies are not satisfactory. Previous studies have shown that STAT3 might be a promising therapeutic target for IPF. Here, we designed several series of compounds and finally synthesized a total of 48 novel compounds as potential STAT3 inhibitors. Notably, compound 10K was the most promising compound with excellent inhibitory activity against STAT3 phosphorylation. Subsequently, the anti-pulmonary fibrosis effect of 10K was further investigated by TGF-ß1-stimulated in vitro cell assay and bleomycin (BLM)-induced pulmonary fibrosis animal models. Specifically, compound 10K inhibited the TGF-ß1 induced fibrotic response and blocked the epithelial-mesenchymal transition (EMT) of A549 cells, and its inhibitory effect was significantly better than that of Stattic. In addition, after oral administration of 10K, the symptoms of IPF in the lung tissue in the prevention and treatment mouse models were significantly reversed, and the efficacy was comparable to that of nintedanib. Moreover, 10K improved BLM-induced imbalance of immune microenvironment in lung tissue. Taken together, these results suggest that 10K could be a potential STAT3 inhibitor for the treatment of IPF.

Design, synthesis and biological evaluation of a series of novel pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as FGFRs-dominant multi-target receptor tyrosine kinase inhibitors for the treatment of gastric cancer.

Gastric cancer is the second most lethal cancer across the world. With the progress in therapeutic approaches, the 5-year survival rate of early gastric cancer can reach > 95%. However, the prognosis and survival time of advanced gastric cancer is still somber. Therefore, more effective targeted therapies for gastric cancer treatment are urgently needed. FGFR, VEGFR and other receptor tyrosine kinases have recently been suggested as potential targets for gastric cancer treatment. We herein report the discovery of pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as a new class of FGFRs-dominant multi-target receptor tyrosine kinase inhibitors. SAR assessment identified the most active compounds 8f and 8k, which showed excellent inhibitory activity against a variety of receptor tyrosine kinases. Moreover, 8f and 8k displayed excellent potency in the SNU-16 gastric cancer cell line. Furthermore, 8f and 8k could inhibit FGFR1 phosphorylation and downstream signaling pathways as well as induce cell apoptosis. In vivo, 8f and 8k suppress tumor growth in the SNU-16 xenograft model without inducing obvious toxicity. These findings raise the possibility that compounds 8f and 8k might serve as potential agents for the treatment of gastric cancer.

Matrix metalloproteinases inhibitors in idiopathic pulmonary fibrosis: Medicinal chemistry perspectives.

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Matrix metalloproteinases (MMPs), promising targets for the treatment of IPF, have been identified as playing a pivotal role in IPF. Although the pathological processes of MMPs and IPF have been verified, there are no MMP inhibitors for the treatment of IPF in the clinic. In this review, we will present the latest developments in MMP inhibitors, including pharmacophores, binding modes, selectivity and optimization strategies. In addition, we will also discuss the future development direction of MMP inhibitors based on emerging tools and techniques.

Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as potent fibroblast growth factor receptor inhibitors.

Abnormal activation of FGFR signaling pathway plays an essential role in various types of tumors. Therefore, targeting FGFRs represents an attractive strategy for cancer therapy. Herein, we report a series of 1H-pyrrolo[2,3-b]pyridine derivatives with potent activities against FGFR1, 2, and 3. Among them, compound 4h exhibited potent FGFR inhibitory activity (FGFR1-4 IC50 values of 7, 9, 25 and 712 nM, respectively). In vitro, 4h inhibited breast cancer 4T1 cell proliferation and induced its apoptosis. In addition, 4h also significantly inhibited the migration and invasion of 4T1 cells. Furthermore, 4h with low molecular weight would be an appealing lead compound which was beneficial to the subsequent optimization. In general, this research has been developing a class of 1H-pyrrolo[2,3-b]pyridine derivatives targeting FGFR with development prospects.

Synthesis and biological evaluation of indazole derivatives as anti-cancer agents.

Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC50 = 0.23-1.15 µM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.

Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway.

The incidence of melanoma is increasing rapidly worldwide. Additionally, new and effective candidates for treating melanoma are needed because of the increase in drug resistance and the high metastatic potential of this cancer. The STAT3 signaling pathway plays a pivotal role in pathogenesis of melanoma, making STAT3 a promising anticancer target for melanoma therapy. Niclosamide, an FDA-approved anti-helminthic drug, has been identified as a potent STAT3 inhibitor that suppresses STAT3 phosphorylation at Tyr705 and its transcript activity. In this study, we evaluated the biological activities of niclosamide in melanoma in vitro and in vivo. Niclosamide potently inhibited the growth of four melanoma cell lines and induced the apoptosis of melanoma cells via the mitochondrial apoptotic pathway. Further, western blot analysis indicated that cell apoptosis was correlated with activation of Bax and cleaved caspase-3 and decreased expression of Bcl-2. Moreover, niclosamide markedly impaired melanoma cell migration and invasion, reduced phosphorylated STAT3Tyr705 levels, and inhibited matrix metalloproteinase-2 and -9 expression. Additionally, in a xenograft model of A375, intraperitoneal administration of niclosamide inhibited tumor growth and tumor weight in a dose-dependent manner without obvious side effects. Histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells and p-STAT3Try705-positive cells and increase in cleaved caspase-3-positive cells. Notably, niclosamide significantly inhibited pulmonary metastasis in a B16-F10 melanoma lung metastasis model, including the number of lung metastatic nodules and lung/body coefficient. Importantly, a marked reduction in myeloid-derived suppressor cells (Gr1+CD11b+) infiltration in the pulmonary metastasis tissue was observed. Taken together, these results demonstrate that niclosamide is a promising candidate for treating melanoma.