Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ.

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.

Ethyl 2-[(Z)-2-benzyl-hydrazin-1-yl-idene]-2-bromo-acetate.

In the title compound, C(11)H(13)BrN(2)O(2), the dihedral angle between the phenyl ring and the almost planar (r.m.s. deviation = 0.011 Å) C-C(Br)=N-N(H)- fragment is 74.94 (16)°. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds, which generate C(6) chains propagating in [010]. Weak aromatic π-π stacking [centroid-centroid separation = 3.784 (3) Å] may also help to consolidate the packing.

Synthesis and antiproliferative activities of 5-azacytidine analogues in human leukemia cells.

Twenty-six 5-azacytidine analogues have been synthesized, including 4-amino- 6-alkyl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 1a-j, 6-amino-4-alkyl/aryl-1- pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 2a-f and 4-amino-6-alkyl-1,3,5-triazin-2- yl-1-thio-pyranosides/ribofuranosides 3a-j. The antiproliferative activities of these synthetic analogues were investigated in human leukemia HL-60 cells. Ribofuranosyl S-nucleoside 3a, a bioisostere of 5-azacytidine, had a similar antiproliferative ability as that of the latter. Introduction of a methyl at the 6 position of 5-azacytidine and/or replacement of the ribofuranosyl moiety with pyranosyl sugars or disaccharides significantly decreased the antiproliferative activities of the 5-azacytidine derivatives. Several compounds with the replacement of pyranosyl sugars enhanced all-trans retinoic acid-induced differentiation ability in human leukemia HL-60 cells.