作者: Taylor, Simon ; Zanelli, Ugo ; Bouix-Peter, Claire ; Maclean, John ; Talbot, Eric ; Campos, Sebastien ; Hacini-Rachinel, Feriel ; Foote, Kevin ; Crosignani, Stefano ; Wang, Shun ; Julia, Valerie ; Harris, Craig ; Nicodeme, Edwige ; Hu, Haiyang

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.

2011-01-01·Journal of Endocrinological Investigation2区 · 医学

The inhibitory effects of PKCθ on adiponectin expression is mediated by ERK in 3T3-L1 adipocytes

2区 · 医学

Article

作者: S. Sun ; J. Lu ; C. Wang ; Y. Bi ; A. Omar ; Y. Liu

The research suggests that adiponectin plays an important role in sensitizing insulin action. It is interesting to find that the lower levels of adiponectin exist in the plasma of obese and Type 2 diabetes subjects and in the adipose tissue of obese, db/db mice, and insulin-resistant individuals. However, the underlying mechanism by which adiponectin expression is inhibited remains largely unknown. In this study, we reported that adipogenesis was inhibited by the stable over-expression of protein kinase C θ (PKCθ) in 3T3-L1 pre - adipocytes. The prolonged treatment of mature 3T3-L1 adipocytes with palmitate, a kind of saturated free fatty acid, reduced adiponectin expression at both mRNA level and protein level, accompanied with the enhanced phosphorylation of PKCθ and extracellular signal-regulated kinase (ERK), and the impaired expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) mRNA. Either PD98059, an ERK inhibitor or PKCθ pseudosubstrate, a specific PKCθ inhibitor, restored palmiate-inhibited PPARγ2 mRNA expression and subsequent adiponectin expression. In addition, the over-expression or activation of PKCθ resulted in the enhanced phosphorylation of ERK in the mature 3T3-L1 adipocytes. PKCθ pseudosubstrate significantly reduced the phorbol 3-myristate 12-acetate (PMA)-induced phosphorylation of ERK. The data suggested that PKCθ-dependent activity of ERK resulted in the impaired expression of PPARγ2 mRNA leading to the reduction of adiponectin expression in the mature 3T3-L1 adipocytes.

2010-11-01·Biochemical and Biophysical Research Communications3区 · 生物学

Oleate and eicosapentaenoic acid attenuate palmitate-induced inflammation and apoptosis in renal proximal tubular cell

3区 · 生物学

Article

作者: Daisuke Koya ; Masami Chin-Kanasaki ; Takashi Uzu ; Yoshihiko Nishio ; Masakazu Haneda ; Naoko Takeda ; Hiroshi Maegawa ; Shinji Kume ; Yuki Tanaka ; Atsunori Kashiwagi ; Toshiro Sugimoto ; Mariko Soumura ; Shin-ichi Araki ; Keiji Isshiki

Free fatty acid (FFA)-bound albumin, which is filtrated through the glomeruli and reabsorbed into proximal tubular cells, is one of the crucial mediators of tubular damage in proteinuric kidney disease. In this study, we examined the role of each kind of FFA on renal tubular damage in vitro and tried to identify its molecular mechanism. In cultured proximal tubular cells, a saturated fatty acid, palmiate, increased the expression of monocyte chemoattractant protein-1 (MCP-1), but this effect was abrogated by co-incubation of monounsaturated fatty acid, oleate, or ω-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). Palmitate led to intracellular accumulation of diacylglycerol (DAG) and subsequent activation of protein kinase C protein family. Among the several PKC inhibitors, rottlerin, a PKCθ inhibitor, prevented palmitate-induced MCP-1 expression via inactivation of NFB pathway. Overexpression of dominant-negative PKCθ also inhibited palmitate-induced activation of MCP-1 promoter. Furthermore, palmitate enhanced PKCθ-dependent mitochondrial apoptosis, which was also prevented by co-incubation with oleate or EPA through restoration of pro-survival Akt pathway. Moreover, oleate and EPA inhibited palmitate-induced PKCθ activation through the conversion of intracellular DAG to triglyceride with the restoration of diacylglycerol acyltransferase 2 expression. These results suggest that oleate and EPA have protective effects against the palmitate-induced renal tubular cell damage by inhibiting PKCθ activation.

100 项与 PKCθ Inhibitor (BMS) 相关的药物交易

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