Fragment-Based Anti-inflammatory Agent Design and Target Identification: Discovery of AF-45 as an IRAK4 Inhibitor to Treat Ulcerative Colitis and Acute Lung Injury.

UC and ALI are inflammatory diseases with limited treatment in the clinic. Herein, fragment-based anti-inflammatory agent designs were carried out deriving from cyclohexylamine/cyclobutylamine and several fragments from anti-inflammatory agents in our lab. AF-45 (IC50 = 0.53/0.60 µM on IL-6/TNF-α in THP-1 macrophages) was identified as the optimal molecule using ELISA and MTT assays from the 33 synthesized compounds. Through mechanistic studies and a systematic target search process, AF-45 was found to block the NF-κB/MAPK pathway and target IRAK4, a promising target for inflammation and autoimmune diseases. The selectivity of AF-45 targeting IRAK4 was validated by comparing its effects on other kinase/nonkinase proteins. In vivo, AF-45 exhibited a good therapeutic effect on UC and ALI, and favorable PK proprieties. Since there are currently no clinical or preclinical trials for IRAK4 inhibitors to treat UC and ALI, AF-45 provides a new lead compound or candidate targeting IRAK4 for the treatment of these diseases.

Discovery of new cinnamic derivatives as anti-inflammatory agents for treating acute lung injury in mice.

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% for  IL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI.

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs.

Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

Design, synthesis and bioactivity evaluation of fisetin derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury.

Acute lung injury (ALI) refers to a common and life-threatening disease attributed to inflammation. However, effective drug treatments have been rare for ALI. Natural products have been considered as a vital source of drug discovery which indicates that it's a workable method to find new anti-inflammatory drugs in natural products. Inspired by the various biological activities of fisetin, we reported the design and synthesis of a series of fisetin derivatives which were also evaluated for their anti-inflammatory activities in J774A.1 macrophages. Most of the obtain derivatives could effectively inhibit the release of IL-6 and TNF-α in vitro experiments without cytotoxicity. The most promising compound 5b exhibited significant in vivo anti-inflammatory activity in the model of LPS-induced ALI in mice. On the whole, this study could provide novel candidates for the treatment of ALI.