INTRODUCTIONPDE2 is a dual-specific enzyme that hydrolyzes two intracellular substrates, cAMP and cGMP. PDE2 is mainly distributed in the brain, which indicates that PDE2 can serve as a potential target for central nervous system diseases without causing other peripheral side effects. Discovery of new mechanisms of PDE2 inhibitors is expected to bring new opportunities for the treatment of central nervous system diseases.AREA COVEREDThis review aims to provide an overview of PDE2 inhibitors reported in patents from 2017 to present.EXPERT OPINIONIn recent years, the development of PDE2 inhibitors and their application in the treatment of brain diseases have received much attention. The main reason is the high expression of PDE2 in the brain, which gives PDE2 a natural advantage as a research target for central nervous system diseases. This review summarizes the scaffolds of PDE2 inhibitors reported in various patents since 2017, as well as the scientific issues that need to be addressed in terms of subtype selectivity and metabolic stability, intending to provide insights for the discovery of highly active and selective PDE2 inhibitors in the future.

2024-08-02·Cancer Discovery

ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer

Article

作者: Arteaga, Carlos L. ; Xu, Yaru ; Li, Xiang ; Barnes, Spencer ; Wang, Yunguan ; Wang, Choushi ; Cheng, Siyuan ; He, Housheng H. ; Zhu, Hong ; Wainwright, Garrett ; Wang, Zhao ; Deng, Su ; Feng, Felix Y. ; Tang, Yitao ; Wang, Zhaoning ; Johnson, Nickolas A. ; Gonzalez, Julisa ; Sjöström, Martin ; Xu, Quanhui ; Liang, Han ; Chen, Yu ; Mukherji, Atreyi ; Metang, Lauren A. ; Hanker, Ariella B. ; Zhu, Guanghui ; Wang, Tao ; Mu, Ping ; Raj, Ganesh V. ; Hofstad, Mia ; Tirado, Carla R. ; Yu, Xinzhe ; Li, Xiaoling ; Jiang, Yuyin ; Yang, Yuqiu

AbstractCancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.Significance: This study reveals a bifurcated role of ZNF397, and a TET2–driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance.

2024-05-01·Biomedicine & Pharmacotherapy

Protective effect of esculentoside A against myocardial infarction via targeting C-X-C motif chemokine receptor 2

Article

作者: Bian, Yehua ; Peng, Jinyong ; Wang, Zhuoya ; Xu, Lina ; Gao, Meng ; Cai, Qing

Myocardial infarction (MI) is the primary cause of cardiac mortality. Esculentoside A (EsA), a triterpenoid saponin, has anti-inflammatory and antioxidant activities. However, its effect on MI remains unknown. In this study, the protective effect and mechanisms of EsA against MI were investigated. EsA significantly alleviated hypoxia-induced HL-1 cell injury, including increasing cell viability, inhibiting reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) and lactate dehydrogenase (LDH) leakage. In mouse MI model by left coronary artery (LAD) ligating, EsA obviously restored serum levels of creatine kinase isoenzymes (CK-MB), cardiac troponin I (cTnI), superoxide dismutase (SOD) and malondialdehyde (MDA). In addition, the cardioprotective effect of EsA was further confirmed by infarct size, electrocardiogram and echocardiography. Mechanistically, the targeted binding relationship between EsA and C-X-C motif chemokine receptor 2 (CXCR2) was predicted by molecular docking and dynamics, and validated by small molecule pull-down and surface plasmon resonance tests. EsA inhibited CXCR2 level both in vitro and in vivo, correspondingly alleviated oxidative stress by suppressing NOX1 and NOX2 and relieved inflammation through inhibiting p65 and p-p65. It demonstrated that EsA could play a cardioprotective role by targeting CXCR2. However, the effect of EsA against MI was abolished in combination with CXCR2 overexpression both in vitro and in vivo. This study revealed that EsA showed excellent cardioprotective activities by targeting CXCR2 to alleviate oxidative stress and inflammation in MI. EsA may function as a novel CXCR2 inhibitor and a potent candidate for the prevention and intervention of MI in the future.

100 项与 PDE2 inhibitor(Dart NeuroScience LLC) 相关的药物交易

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