Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation.

The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 µM. Among them, ZDS20 was identified as the most effective inhibitor with low micromolar activity (IC50 = 3.27 µM). Altogether, ZDS20 carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.

Carbene-Catalyzed [4+2] Cycloaddition of Cyclobutenones and Isatins for Quick Access to Chiral Chlorine-Containing Spirocyclic δ-Lactones.

Here we report a carbene-catalyzed enantio- and diastereoselective [4+2] cycloaddition reaction of cyclobutenones with isatins for the quick and efficient synthesis of spirocyclic δ-lactones bearing a chiral chlorine. A broad range of substrates with various substitution patterns proceed smoothly in this reaction, with the spirooxindole δ-lactone products afforded in generally good to excellent yields and optical purities under mild reaction conditions.

Discovery of LAH-1 as potent c-Met inhibitor for the treatment of non-small cell lung cancer.

ABSTRCTDysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N-(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (LAH-1), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.

Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3Kα inhibitors.

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within.

Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity.

Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms ß, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.

Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor.

IDH1 mutations are closely related to the development and progression of various human cancers, such as glioblastoma, sarcoma, and acute myeloid leukemia. By screening dozens of reported natural compounds using both wild-type and mutant IDH1 enzymatic assays, we discovered Licochalcone A is a selective inhibitor to the R132C-mutant IDH1 with an IC50 value of 5.176 µM, and inhibits the proliferation of sarcoma HT-1080 cells with an IC50 value of 10.75 µM. Suggested by the molecular docking results, Licochalcone A might occupy the allosteric pocket between the two monomers of IDH1 homodimer, and the R132H mutation was unfavorable for the binding of Licochalcone A with the IDH1 protein, as compared to the R132C mutation. Revealed by the RNA-Seq data analysis, the Cell Cycle pathway was the most over-represented pathway for HT-1080 cells treated with Licochalcone A. Consistent with these results, Licochalcone A induced apoptosis and cell cycle arrest of HT-1080 cells, while it showed minimal effect against the proliferation of normal RCTEC cells. The discovery of Licochalcone A as a mutation-selective IDH1 inhibitor can serve as a promising starting point for the development of mutation-selective anti-tumor lead compounds targeting IDH1.

Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors.

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and cellular assays. The most promising analog, 58 (c-Met IC50=1.42 nM), displayed 2.1-, 8.6-fold increase against H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure-activity relationships revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for antitumor activity.

Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors.

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five cancer cell lines (A549, H460, HT-29, MKN-45, and U87MG). Most compounds showed weak to excellent antiproliferative activity. The most promising analog, 40 (c-Met IC50 = 1.86 nM), displayed 1.3-, 6.8-, 1.5-, 3.5-fold increase against HT-29, H460, A549 and U87MG cell lines, respectively, compared with Foretinib. An analysis of structure-activity relationships revealed that an acylhydrazone scaffold with an unsubstituted sp(2) hybridized carbon adjacent to the 4-CF3 phenyl ring is favorable for antitumor activity.

Synthesis and biological evaluation of novel 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties as potent antitumor agents.

A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50 = 0.08, 0.36, 0.97 µM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50 = 3.61, 2.19, 2.32 µM), and 17, 3.2, and 2.9 times better than PAC-1 (IC50 = 1.36, 1.17, 2.83 µM) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase.