Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Sivakumaren, Sindhu Carmen; Shim, Hyeseok; Zhang, Tinghu; Ferguson, Fleur M.; Lundquist, Mark R.; Browne, Christopher M.; Seo, Hyuk‐Soo; Paddock, Marcia N.; Manz, Theresa D.; Jiang, Baishan; Hao, Mingfeng; Krishnan, Pranav; Wang, Diana G.; Yang, Tong; Kwiatkowski, Nicholas; Ficarro, Scott B.; Cunningham, James M.; Marto, Jarrod A.; Dhe‐Paganon, Sirano; Cantley, Lewis C.; Gray, Nathanael S.

doi:10.1016/j.chembiol.2020.02.003

Cited by 39 publications

(54 citation statements)

References 55 publications

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“…While this paper was under review, two new classes of chemical probes targeting PI5P4K were reported (62)(63)(64). Although these inhibitors appear to have weaker affinities than CC260 in vitro, one of them can react covalently with a free cysteine adjacent to the lipid kinase's active site, which should enhance its effectiveness and selectivity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells

Chen

Tjin

Gao

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase α and β (PI5P4Kα and PI5P4Kβ) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kα/β kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kαβ inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs.

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells

Chen

Tjin

Gao

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…All things considered, in the recent past, PI5P4Ks and their product PI-4,5-P 2 have risen from insignificance to being without a doubt one of the key metabolic sensors and regulators within the cell as well as pivotal players for interorganelle communication necessary for cell survival. With drugs being developed against these kinases (Davis et al, 2013;Clarke et al, 2015;Al-Ramahi et al, 2017;Kitagawa et al, 2017;Manz et al, 2020;Sivakumaren et al, 2020;Chen et al, 2021), targeting them in the near future in various diseases is looking brighter.…”

Section: Health and Disease: Pi5p4ks Emerge As Exciting Targetsmentioning

confidence: 99%

Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface

Ravi

Palamiuc

Emerling

2022

Front. Cell Dev. Biol.

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While organelles are individual compartments with specialized functions, it is becoming clear that organellar communication is essential for maintaining cellular homeostasis. This cooperation is carried out by various interactions taking place on the membranes of organelles. The membranes themselves contain a multitude of proteins and lipids that mediate these connections and one such class of molecules facilitating these relations are the phospholipids. There are several phospholipids, but the focus of this perspective is on a minor group called the phosphoinositides and specifically, phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2). This phosphoinositide, on intracellular membranes, is largely generated by the non-canonical Type II PIPKs, namely, Phosphotidylinositol-5-phosphate-4-kinases (PI5P4Ks). These evolutionarily conserved enzymes are emerging as key stress response players in cells. Further, PI5P4Ks have been shown to modulate pathways by regulating organelle crosstalk, revealing roles in preserving metabolic homeostasis. Here we will attempt to summarize the functions of the PI5P4Ks and their product PI-4,5-P2 in facilitating inter-organelle communication and how they impact cellular health as well as their relevance to human diseases.

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“…PIP4K2A is a member of the phosphatidylinositol-5-phosphate 4-kinase family and mediates secretion, cell proliferation, differentiation, and motility ( Rameh et al, 1997 ). It is associated with cancer ( Sivakumaren et al, 2020 ) and it has also been examined for potential involvement in schizophrenia, but only a minor association was reported ( Thiselton et al, 2010 ). PIP4K2A rs10828317, rs746203, and rs8341 have been investigated for potential association with TD in a cohort of 491 patients of Siberian origin, but only rs10828317 was associated with TD development ( Fedorenko et al, 2014 ).…”

Section: Pharmacogenomic Studies Focusing On the Association Between Tardive Dyskinesia And Genes Involved In The Pharmacodynamicsmentioning

confidence: 99%

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

2022

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Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients’ clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.

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Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Cited by 39 publications

References 55 publications

Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells

Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells

Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

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