The endothelin (ET) signaling system is comprised of three endothelin peptides (ET-1, -2 and -3) and two corresponding endothelin-A and -B receptors (ET_AR and ET_BR), which belong to the G-protein coupled receptor (GPCR) superfamily. The endothelin axis, as this system is also referred to, contributes to the maintenance of vascular tone, functions as regulator of inflammation and proliferation and helps in balancing water homeostasis. In pathological settings, the ET axis is known to contribute to endothelial activation in cardiovascular diseases, to cell proliferation, chemoresistance and metastasis in cancer and to inflammation and fibrosis in renal disease. Antagonists of ET_AR and ET_BR, either subtype-specific compounds or substances with high affinity to both receptors, have been developed for more than 30 years. In the preclinical context, in vivo imaging of endothelin receptor expression has been utilized to assess ET-axis contribution to e.g. cancer or myocardial infarction. In this work, we present the development and synthesis of two novel ET_BR-specific fluorescent probes, based on the available antagonists BQ788 and IRL2500 and their preliminary evaluation in a breast cancer context.

01 Apr 2021·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Inhibition of Notch1 signaling reduces hepatocyte injury in nonalcoholic fatty liver disease via autophagy

Q3 · BIOLOGY

Article

Author: Tian, Tian ; Zhang, Min ; Wu, Pengbo ; Li, Ming ; Liao, Xingchen ; Guo, Yitian ; Tan, Shiyun

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide and an urgent target for clinical intervention. Notch1 signaling pathway activity was found to be related to the severity of NAFLD, but the specific mechanism is not precise. Here, we investigated the potential mechanisms of Notch1 signaling in the development of NAFLD. Firstly, we found that Notch1 signaling is activated in free fatty acids-treated HepG2 cells accompanied by lipid accumulation, apoptosis, oxidative stress, and mitochondrial damage, which could be alleviated by Notch1 inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). In the meantime, we found that administration of DAPT activated the autophagy pathway in NAFLD. Furthermore, the use of autophagy inhibitor chloroquine reversed the DAPT-mediated protective effect in NAFLD. All our results uncover a vital role of Notch1 in hepatocyte injury and metabolism of NAFLD, giving rise to a new sight for NAFLD treatment by regulation of Notch signaling and autophagy pathway.

12 Jul 2018·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin

Q3 · MEDICINE

Article

Author: Zapol, Warren M. ; Liu, Chen ; Goldstein, Sara R. ; Nakagawa, Akito ; Safo, Martin K. ; Winkler, Jeffrey D.

Carbon monoxide (CO) poisoning causes between 5,000-6,000 deaths per year in the US alone. The development of small molecule allosteric effectors of CO binding to hemoglobin (Hb) represents an important step toward making effective therapies for CO poisoning. To that end, we have found that the synthetic peptide IRL 2500 enhances CO release from COHb in air, but with concomitant hemolytic activity. We describe herein the design, synthesis, and biological evaluation of analogs of IRL 2500 that enhance the release of CO from COHb without hemolysis. These novel structures show improved aqueous solubility and reduced hemolytic activity and could lead the way to the development of small molecule therapeutics for the treatment of CO poisoning.

100 Deals associated with IRL-2500

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Preclinical	US	Novartis AG	01 Jan 1995

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