Pulmonary artery smooth muscle cell phenotypic switching: A key event in the early stage of pulmonary artery hypertension.

Pulmonary arterial hypertension (PAH) is a currently incurable pulmonary vascular disease. Since current research on PAH is mainly aimed at the middle and late stages of disease progression, no satisfactory results have been achieved. This has led researchers to focus on the early stages of PAH. This review highlights for the first time a key event in the early stages of PAH progression, namely, the occurrence of pulmonary arterial smooth muscle cell (PASMC) phenotypic switching. Summarizing the related reports of phenotypic switching provides new perspectives and directions for the early pathological progression and treatment strategies for PAH.

Dual inhibitors of ASK1 and PDK1 kinases: Design, synthesis, molecular docking and mechanism studies of N-benzyl pyridine-2-one containing derivatives as anti-fibrotic agents.

Utilizing fragment-based hybrid designing strategies, 24 N-benzyl pyridine-2-one containing derivatives were synthesized by successfully incorporating 6-(4H-1,2,4-triazol-3-yl) pyridin-2-amine of scaffold of ASK1 inhibitor (GS-444217). These newly synthesized compounds were screened in cell-free ASK1 and PDK1 kinase and cellular vitality assays. Among all compounds tested, both 21c and 21d displayed single digit potency of 9.13, 1.73 nM in inhibiting ASK1, and exhibited excellent enzyme inhibitory activity against PDK1 (the inhibition rates at 10 µM were 13.63% and 23.80%, respectively). Specifically, both compounds inhibited the TGF-ß1 induced fibrotic response and blocked the up-regulated protein expression levels of ASK1-p38/JNK signaling pathways and possessed the potency in reducing PDK1/Akt phosphorylation. The results herein showed the potential lead characteristics of 21c or 21d as dual inhibitors ASK1/PDK1 kinases.