Identification of ARUK2002821 as an isoform-selective PI5P4Kα inhibitor

Willems, Henriëtte M. G.; Edwards, Simon; Boffey, Helen K.; Chawner, Stephen John; Green, Christopher; Romero, T.; Winpenny, David; Skidmore, John; Clarke, Jonathan H.; Andrews, Stephen P.

doi:10.1039/d3md00039g

Cited by 3 publications

(5 citation statements)

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“…The rationally-designed compound 18 was found to have improved PI5P4Kα activity compared to 17 but diminished PI5P4Kγ+ activity (Table 3). An alternative potent PI5P4Kα inhibitor with a 2,4-dimethylphenyl group, “compound 25 ”, 33 was also merged onto the thienylpyrimidine core to give the resulting compound 19 . Both 18 and 19 are dual PI5P4Kα/γ+ inhibitors, as predicted.…”

Section: Resultsmentioning

confidence: 99%

“…Lipophilic substituents at R 2 have previously been found to be important for PI5P4Kα inhibition. 33 As such, a variety of other lipophilic groups was tested at this position (Table 3). Compounds 20 and 21 were modest dual inhibitors and an interesting SAR trend was observed for the series of small aliphatic groups for 22–24 , which increased in both PI5P4Kα and PI5P4Kγ+ activity with increasing size of the para substituent.…”

Section: Resultsmentioning

confidence: 99%

“…Several recent reports detail inhibitors for PI5P4Ks, not only pan-specific 25–29 but also isoform specific. 30–34 Emerging tools are also being developed for dual-specific inhibitors for PI5P4Kα and PI5P4Kβ 22,35 and methods have also been reported for removing protein completely in cells using PROTAC systems, such as JWZ-1-80 for PI5P4Kγ, 36 which will be useful to interrogate non-catalytic roles. Here we present a new tool that can be used to investigate the impact of dual inhibition of both the PI5P4Kα and PI5P4Kγ isoforms.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported PI5P4Kγ-selective inhibitors including ARUK2001607 ( 1 ) which was derived from virtual screening hit 2 , 30 as well as PI5P4Kα-selective inhibitors including tool compound ARUK2002821 ( 3 ) which was derived from virtual screening hit 4 (ref. 33) (Table 1). During the course of those studies, we also became interested in developing dual PI5P4Kα–PI5P4Kγ inhibitors as probe molecules.…”

Section: Introductionmentioning

confidence: 99%

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The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K)

Aldred,

Rooney,

Willems

et al. 2023

RSC Med. Chem.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K)

Aldred,

Rooney,

Willems

et al. 2023

RSC Med. Chem.

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“…For example, I-Ome Tyrphostin AG-538 is identified as the ATP-competitive inhibitor of PIP4Kα ( 89 ). BAY-091 and BAY-297 serve as the valuable inhibitors of the kinase PIP4K2A ( 90 ), ARUK2002821 is also identified as an selective PIP4Kα inhibitor and has broad selectivity against lipid and protein kinases ( 91 ). Another noteworthy inhibitor is SAR088, representing the first orally available and in vivo active PIP4K2B inhibitor ( 92 ).…”

Section: Insight Into the Pip5k And Pip4k Familymentioning

confidence: 99%

Lipid kinases PIP5Ks and PIP4Ks: potential drug targets for breast cancer

Jin,

Xue

2023

Front. Oncol.

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Phosphoinositides, a small group of lipids found in all cellular membranes, have recently garnered heightened attention due to their crucial roles in diverse biological processes and different diseases. Among these, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), the most abundant bis-phosphorylated phosphoinositide within the signaling system, stands notably connected to breast cancer. Not only does it serve as a key activator of the frequently altered phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer, but also its conversion to phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) is an important direction for breast cancer research. The generation and degradation of phosphoinositides intricately involve phosphoinositide kinases. PI(4,5)P2 generation emanates from the phosphorylation of PI4P or PI5P by two lipid kinase families: Type I phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and Type II phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). In this comprehensive review, we focus on these two lipid kinases and delineate their compositions and respective cellular localization. Moreover, we shed light on the expression patterns and functions of distinct isoforms of these kinases in breast cancer. For a deeper understanding of their functional dynamics, we expound upon various mechanisms governing the regulation of PIP5Ks and PIP4Ks activities. A summary of effective and specific small molecule inhibitors designed for PIP5Ks or PIP4Ks are also provided. These growing evidences support PIP5Ks and PIP4Ks as promising drug targets for breast cancer.

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Targeting phosphoinositide signaling in cancer: relevant techniques to study lipids and novel avenues for therapeutic intervention

Llorente,

Loughran,

Emerling

2023

Front. Cell Dev. Biol.

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Phosphoinositides serve as essential players in numerous biological activities and are critical for overall cellular function. Due to their complex chemical structures, localization, and low abundance, current challenges in the phosphoinositide field include the accurate measurement and identification of specific variants, particularly those with acyl chains. Researchers are intensively developing innovative techniques and approaches to address these challenges and advance our understanding of the impact of phosphoinositide signaling on cellular biology. This article provides an overview of recent advances in the study of phosphoinositides, including mass spectrometry, lipid biosensors, and real-time activity assays using fluorometric sensors. These methodologies have proven instrumental for a comprehensive exploration of the cellular distribution and dynamics of phosphoinositides and have shed light on the growing significance of these lipids in human health and various pathological processes, including cancer. To illustrate the importance of phosphoinositide signaling in disease, this perspective also highlights the role of a family of lipid kinases named phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), which have recently emerged as exciting therapeutic targets for cancer treatment. The ongoing exploration of phosphoinositide signaling not only deepens our understanding of cellular biology but also holds promise for novel interventions in cancer therapy.

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Identification of ARUK2002821 as an isoform-selective PI5P4Kα inhibitor

Abstract: The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders....

Cited by 3 publications

References 30 publications

The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K)

The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K)

Lipid kinases PIP5Ks and PIP4Ks: potential drug targets for breast cancer

Targeting phosphoinositide signaling in cancer: relevant techniques to study lipids and novel avenues for therapeutic intervention

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