Discovery and Structure–Activity Relationship Study of (<i>Z</i>)-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Manz, Theresa D.; Sivakumaren, Sindhu Carmen; Ferguson, Fleur M.; Zhang, Tinghu; Yasgar, Adam; Seo, Hyuk‐Soo; Ficarro, Scott B.; Card, Joseph D.; Shim, Hyeseok; Miduturu, Chandrasekhar V.; Simeonov, Anton; Shen, Min; Marto, Jarrod A.; Dhe‐Paganon, Sirano; Cantley, Lewis C.; Gray, Nathanael S.

doi:10.1021/acs.jmedchem.0c00227

Cited by 19 publications

(22 citation statements)

References 42 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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“…Of the compounds retested, 580 were confirmed to be active in this dose−response qHTS assay, representing a 43% confirmation rate. Importantly, almost all of these compounds were inactive in previous NCATS screens against PI4K2A and PI5P4Ka which also used the ADP-Glo format, 13,14 suggesting that they are selective against other lipid kinases and not assay artifacts.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening

Liao

Heitmann

et al. 2021

ACS Pharmacol. Transl. Sci.

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Inositol hexakisphosphate kinases (IP6Ks) catalyze pyrophosphorylation of inositol hexakisphosphate (IP6) into inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7), which is involved in numerous areas of cell physiology including glucose homeostasis, blood coagulation, and neurological development. Inhibition of IP6Ks may be effective for the treatment of Type II diabetes, obesity, metabolic complications, thrombosis, and psychiatric disorders. We performed a high-throughput screen (HTS) of 158 410 compounds for IP6K1 inhibitors using a previously developed ADP-Glo Max assay. Of these, 1206 compounds were found to inhibit IP6K1 kinase activity by more than 25%, representing a 0.8% hit rate. Structural clustering analysis of HTS-active compounds, which were confirmed in the dose–response testing using the same kinase assay, revealed diverse clusters that were feasible for future structure–activity relationship (SAR) optimization to potent IP6K inhibitors. Medicinal chemistry SAR efforts in three chemical series identified potent IP6K1 inhibitors which were further validated in an orthogonal LC-MS IP7 analysis. The effects of IP6K1 inhibitors on cellular IP7 levels were further confirmed and were found to correlate with cellular IP6K1 binding measured by a high-throughput cellular thermal shift assay (CETSA).

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“…In fact, efforts have been made to identify and characterize pan inhibitors [33,34] as well as isoform specific inhibitors of PI5P4Ks [75,76], and over the years, there have been reports of more potent and selective small molecule inhibitors [60,[77][78][79], strengthening the evidence for efficient druggability of the PI5P4Ks. Recently in an attempt to identify drugs that are selectively lethal to cancer cells but not to normal cells, a novel compound, a131, was identified and interestingly, the group discovered that the target of the a131 compound is indeed the PI5P4Ks and it selectively regulated the cell cycle entry of Ras-activated cancer cells resulting in their death through mitotic catastrophe, while causing reversible growth arrest in normal cells [77].…”

Section: Targeting Pi5p4ks With Small Molecule Inhibitorsmentioning

confidence: 99%

“…In a follow-up study by the same group, they sought to find reversible inhibitors of PI5P4Ks so that issues associated with acquired resistance of tumor cells could be avoided. Among a library of approximately 6000 kinase inhibitors, they identified a potent inhibitor and further developed a pan-PI5P4K inhibitor with better selectivity [78]. Most recently, a noncovalent dual PI5P4Ka/b inhibitor, CC260, was identified using a high-throughput screen among 5759 small molecules.…”

Section: Targeting Pi5p4ks With Small Molecule Inhibitorsmentioning

confidence: 99%

Expanding role of PI5P4Ks in cancer: A promising druggable target

2021

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Cancer cells are challenged by a myriad of microenvironmental stresses, and it is their ability to efficiently adapt to the constantly changing nutrient, energy, oxidative, and/or immune landscape that allows them to survive and proliferate. Such adaptations, however, result in distinct vulnerabilities that are attractive therapeutic targets. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are a family of druggable stress-regulated phosphoinositide kinases that become conditionally essential as a metabolic adaptation, paving the way to targeting cancer cell dependencies. Further, PI5P4Ks have a synthetic lethal interaction with the tumor suppressor p53, the loss of which is one of the most prevalent genetic drivers of malignant transformation. PI5P4K's emergence as a crucial axis in the expanding landscape of phosphoinositide signaling in cancer has already stimulated the development of specific inhibitors. Thus, a better understanding of the biology of the PI5P4Ks will allow for targeted and effective therapeutic interventions. Here, we attempt to summarize the mounting roles of the PI5P4Ks in cancer, including evidence that targeting them is a therapeutic vulnerability and promising nextin-line treatment for multiple cancer subtypes.

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Discovery and Structure–Activity Relationship Study of (Z)-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Cited by 19 publications

References 42 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

Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening

Expanding role of PI5P4Ks in cancer: A promising druggable target

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