Synthesis and structure–activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent β isoform selective phosphatidylinositol 3-kinase inhibitors

Sanchez, Robert M.; Erhard, Karl F.; Hardwicke, Mary Ann; Lin, Hong; McSurdy-Freed, Jeanelle; Plant, Ramona; Raha, Kaushik; Rominger, Cynthia M.; Schaber, Michael D.; Spengler, Michael D.; Moore, Michael L.; Yu, Hongyi; Luengo, Juan I.; Tedesco, Rosanna; Rivero, Ralph A.

doi:10.1016/j.bmcl.2012.03.039

Cited by 48 publications

(27 citation statements)

References 13 publications

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“…Consistent with this, BYL719 induced a reduction in levels of phosphorylated Akt ( Figure 4C ). No alteration in branching was seen when whole explants were cultured with an inhibitor of the beta isoform of PI3K, GSK2636771 [34] , over 48 hours ( Figure 4A, B ). Equally, no reduction in phosphorylated Akt was observed from explants cultured with GSK2636771, suggesting a lack of involvement of the beta isoform in this system.…”

Section: Resultsmentioning

confidence: 99%

Phosphoinositide 3-Kinase Alpha-Dependent Regulation of Branching Morphogenesis in Murine Embryonic Lung: Evidence for a Role in Determining Morphogenic Properties of FGF7

et al. 2014

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Branching morphogenesis is a critical step in the development of many epithelial organs. The phosphoinositide-3-kinase (PI3K) pathway has been identified as a central component of this process but the precise role has not been fully established. Herein we sought to determine the role of PI3K in murine lung branching using a series of pharmacological inhibitors directed at this pathway. The pan-class I PI3K inhibitor ZSTK474 greatly enhanced the branching potential of whole murine lung explants as measured by an increase in the number of terminal branches compared with controls over 48 hours. This enhancement of branching was also observed following inhibition of the downstream signalling components of PI3K, Akt and mTOR. Isoform selective inhibitors of PI3K identified that the alpha isoform of PI3K is a key driver in branching morphogenesis. To determine if the effect of PI3K inhibition on branching was specific to the lung epithelium or secondary to an effect on the mesenchyme we assessed the impact of PI3K inhibition in cultures of mesenchyme-free lung epithelium. Isolated lung epithelium cultured with FGF7 formed large cyst-like structures, whereas co-culture with FGF7 and ZSTK474 induced the formation of defined branches with an intact lumen. Together these data suggest a novel role for PI3K in the branching program of the murine embryonic lung contradictory to that reported in other branching organs. Our observations also point towards PI3K acting as a morphogenic switch for FGF7 signalling.

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Section: Resultsmentioning

confidence: 99%

Phosphoinositide 3-Kinase Alpha-Dependent Regulation of Branching Morphogenesis in Murine Embryonic Lung: Evidence for a Role in Determining Morphogenic Properties of FGF7

et al. 2014

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“…Lin et al (GlaxoSmithKline) have reported [94, 95] the discovery of imidazopyrimidinone (294, PI3Kα/β/γ/δ IC 50 = 2.0/0.001/0.008/1 µM) and triazolopyrimidinone (295, PI3Kα/β/γ/δ IC 50 = 0.32/0.0003/0.004/0.06 µM), as novel potent PI3Kβ selective inhibitors, while with poor pharmacokinetic profile. Then they designed [96] thiazolopyrimidinones (296), with a substituted benzyl group at the N1-position to induce the selectivity-pocket formed by Met-779 and Trp-787, a morpholine as the hinge binder and a carbonyl group to interact with the back-pocket.…”

Section: Pyridines Quinolines Indoles and Indazolesmentioning

confidence: 99%

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

Liu

Wan

et al. 2016

Oncotarget

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“…Original samples from the PKIS were obtained from GSK. The compounds GW301784X, GW837331X, GW406108X, GSK2358994A, GSK846226A and GW429374A were synthesised according to previously published methods [20][21][22][23][24][25]. Protein kinases (ULK1, VPS34 and AMPK α1β2ɣ1) and SAMS peptide were purchased from MRC PPU Reagents and Services, Dundee, Scotland.…”

Section: Reagentsmentioning

confidence: 99%

The identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets

Zachari

Rainard

Pandarakalam³

et al. 2020

Biochemical Journal

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Autophagy is a critical cellular homeostatic mechanism, the dysfunction of which has been linked to a wide variety of disease states. It is regulated through the activity of specific kinases, in particular Unc-51 like autophagy activating kinase 1 (ULK1) and Phosphatidylinositol 3-kinase vacuolar protein sorting 34 (VPS34), which have both been suggested as potential targets for drug development. To identify new chemical compounds that might provide useful chemical tools or act as starting points for drug development, we screened each protein against the Published Kinase Inhibitor Set (PKIS), a library of known kinase inhibitors. In vitro screening and analysis of the published selectivity profiles of the hits informed the selection of three relatively potent ATP-competitive inhibitors against each target that presented the least number of off-target kinases in common. Cellular assays confirmed potent inhibition of autophagy in response to two of the ULK1 inhibitors and all three of the VPS34 inhibitors. These compounds represent not only a new resource for the study of autophagy but also potential chemical starting points for the validation or invalidation of these two centrally important autophagy kinases in disease models.

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Synthesis and structure–activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent β isoform selective phosphatidylinositol 3-kinase inhibitors

Cited by 48 publications

References 13 publications

Phosphoinositide 3-Kinase Alpha-Dependent Regulation of Branching Morphogenesis in Murine Embryonic Lung: Evidence for a Role in Determining Morphogenic Properties of FGF7

Phosphoinositide 3-Kinase Alpha-Dependent Regulation of Branching Morphogenesis in Murine Embryonic Lung: Evidence for a Role in Determining Morphogenic Properties of FGF7

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

The identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets

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