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.

Research progress in quinazoline derivatives as multi-target tyrosine kinase inhibitors

Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), are involved in multiple human tumors. Therefore, RTKs are attractive targets for various antitumor strategies. Two classes of tyrosine kinase antagonists were applied in the clinic for monoclonal antibodies and small-molecule tyrosine kinase inhibitors. A well-studied class of small-molecule inhibitors is represented by 4-anilinoquinazolines, exemplified by gefitinib and erlotinib as mono-targeted EGFR inhibitors, which were approved for the treatment of non-small-cell lung cancer. Mono-target drugs may result in drug resistance and the innovation of multi-target drugs has grown up to be an active field. Recent advances in research on antitumor bioactivity of 4-anilino(or phenoxy)quinazoline derivatives with multiple targets are reviewed in this paper. At the same time, synthetic methods of quinazolines were introduced from the point of building the ring skeleton and based on the types of reaction.

Synthesis and evaluation of the antitumor activity of highly functionalised pyridin-2-ones and pyrimidin-4-ones

The methods for selective synthesis of two novel types of compounds including pyridin-2-ones 3 and pyrimidin-4-ones 4 were developed. The antitumor bioactivity screening showed that certain compounds had potent antitumor activity.

Screening of Antitumor Bioactivity of Fungi Associated with Macro Algae and Sponge from Indrayanti Beach, Jogjakarta

This research was aimed to isolate marine derived-fungi which associated with macro algae and sponge from Indrayanti Beach, Jogjakarta and to screen the antitumor (T47D and HeLa) bioactivity of the fungi extracts. Three solid media of MEA (malt extract agar), GPY (glucose peptone yeast) and MFM (minimal fungi medium) were used as isolation medium. Each of the pure fungi isolates was then cultivated in 100 ml of liquid medium for 4 weeks at room temperature (27-28°C) in static conditions. The antitumor activity of the fungi extracts were tested against breast tumor cells (T47D) and cervical cancer cells (HeLa) using Thiazolyl Blue Tetrazolium Blue (MTT) assay method. A number of 21 isolates of fungi were isolated from 4 macro algae and 1 sponge samples. The identification of fungi isolate was conducted using combination of molecular approach (ITS1-5.8S-ITS4 DNA regions) and macro-micro morphological characteristics. Among those 21 marine fungi species isolated, MFGK-21 extract showed the best anti-servical tumor (HeLa) with an IC50 value of 240.1 µg/ml and MFGK-27 extract showed the best anti-breast tumor (T47D) with an IC50 value of 59.6 µg/ml. The MFGK-21 fungi isolate was identified as Penicillium steckii, while the MFGK-27 fungi isolate was identified as Aspergillus sydowii.

Design, Synthesis and Biological Evaluation of Sunitinib Analogues to Improve Aqueous Solubility

In order to improve aqueous solubility of Sunitinib, based on the structure-activity relationship, four analogues were designed and synthesized. The obtained structures were identified by1H NMR, MS and elemental analysis.In vitroevaluation of antitumor bioactivity was performed by MTT method. All of synthesized compounds showed antitumor activities, especially, compounds A1, which were better than or equal to the antitumor activity of positive control.

Design, Syntheses and Biological Evaluation of 3-Arylurea-5-Fluoroindolin-2-One Derivatives

Sixteen 3-arylurea-5-fluoroindolin-2-one derivatives were designed according to the principle of fragment based drug discovery and synthesized with 5-fluoroisatin as the starting material. The obtained structures were identified by 1H NMR, MS and elemental analysis. In vitro evaluation of antitumor bioactivity was performed by MTT method. Most of synthesized compounds showed antitumor activities, especially, activities of 6a, 6h, and 6j in tumor inhibition were better than others.

Design, Syntheses and Biological Evaluation of 5-Fluoroindolin-2-One Derivatives with Urea Linkage

Nine 5-fluoroindolin-2-one derivatives with urea linkage were designed and synthesized. The obtained structures were identified by 1H NMR, MS and elemental analysis. In vitro evaluation of antitumor bioactivity was performed by MTT method. Most of synthesized compounds showed antitumor activities, especially, compounds 6e and 6f, which were better than or equal to the antitumor activity of positive control.