Phosphatidyl inositol (4,5)-bisphosphate (PI(4,5)P) plays several key roles in human biology and the lipid kinase that produces PI(4,5)P, PIP5K, has been hypothesized to provide a potential therapeutic target of interest in the treatment of cancers. To better understand and explore the role of PIP5K in human cancers there remains an urgent need for potent and specific PIP5K inhibitor molecules. Following a high throughput screen of the AstraZeneca collection, a novel, moderately potent and selective inhibitor of PIP5K, 1, was discovered. Detailed exploration of the SAR for this novel scaffold resulted in the considerable optimization of both potency for PIP5K, and selectivity over the closely related kinase PI3Kα, as well as identifying several opportunities for the continued optimization of drug-like properties. As a result, several high quality in vitro tool compounds were identified (8, 20 and 25) that demonstrate the desired biochemical and cellular profiles required to aid better understanding of this complex area of biology.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2021.116557 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Unraveling the Molecular Mechanisms of Blueberry Root Drought Tolerance Through Yeast Functional Screening and Metabolomic Profiling.
Plants (Basel)
December 2024
College of Life Sciences, Zhejiang Normal University, Jinhua 321004, China.
Blueberry plants are among the most important fruit-bearing shrubs, but they have shallow, hairless roots that are not conducive to water and nutrient uptake, especially under drought conditions. Therefore, the mechanism underlying blueberry root drought tolerance should be clarified. Hence, we established a yeast expression library comprising blueberry genes associated with root responses to drought stress.
View Article and Find Full Text PDFComprehensive analysis of proteomic and biochemical responses of Daphnia magna to short-term exposure to polystyrene microplastic particles.
Ecotoxicol Environ Saf
December 2024
Center for Environmental Safety Research, Division of Gyeongnam Bio-Environmental Research, Korea Institute of Toxicology, Jinju 52834, Republic of Korea. Electronic address:
Microplastic (MP) represent a pervasive and escalating threat to aquatic ecosystems, impacting organisms from cellular to population levels. To investigate the immediate molecular impacts of MP exposure, we exposed Daphnia magna, a keystone species in freshwater ecosystems, to polystyrene microplastic particles (5 μm, 5 μg/L) for 48 h. Through proteomic and biochemical analyses, we identified extensive disruptions in key physiological pathways.
View Article and Find Full Text PDFSilencing CaPIP5K4-1 leads to decreased male fertility in Capsicum annuum L.
Planta
December 2024
Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing Botanical Garden, Mem. Sun Yat-Sen, Nanjing, 210014, China.
Phosphatidylinositol 4-phosphate 5-kinase gene CaPIP5K4-1 is highly expressed in the pepper anthers. Virus-induced gene silencing of CaPIP5K4-1 leads to reduced male fertility in pepper. The phosphatidylinositol 4-phosphate 5-kinase (PIP5K) is a pivotal enzyme in the phosphatidylinositol signaling pathway, and its crucial involvement in both plant development and stress response has been established.
View Article and Find Full Text PDFOsPIPK-FAB, A Negative Regulator in Rice Immunity Unveiled by OsMBL1 Inhibition.
Rice (N Y)
November 2024
State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops and Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
Phosphatidylinositol signaling system plays a crucial role in plant physiology and development, phosphatidylinositol phosphate kinases (PIPKs) are one of the essential enzymes responsible for catalyzing the synthesis of phosphatidylinositol bisphosphate (PIP2) within this signaling pathway. However, its mechanism of signal transduction remains poorly exploited in plants. OsMBL1, a jacalin-related mannose-binding lectin in rice, plays a crucial role in plant defense mechanisms, acting as a key component of the pattern-triggered immunity (PTI) pathway.
View Article and Find Full Text PDFInvestigation of the Roles of Phosphatidylinositol 4-Phosphate 5-Kinases 7,9 and Wall-Associated Kinases 1-3 in Responses to Indole-3-Carbinol and Biotic Stress in Arabidopsis Thaliana.
Biomolecules
October 2024
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Article Synopsis
- * A study utilized a genetic screening method to explore how I3C affects plants, identifying two specific plant lines that respond differently to I3C.
- * Both identified lines show distinct responses linked to different kinase families, affecting their tolerance to I3C while maintaining the compound's interference with auxin signaling, suggesting alternative pathways for I3C's effects on plant development and stress responses.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!