- Discovery and structure-activity relationship study of (z)-5-methylenethiazolidin-4-one derivatives as potent and selective pan-phosphatidylinositol 5-phosphate 4-kinase inhibitors
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Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted in compounds with low- to sub-micromolar potencies. Here, we report the identification of CVM-05-002 using a high-throughput screen of PI5P4Kα against our in-house kinase inhibitor library. CVM-05-002 is a potent and selective inhibitor of PI5P4Ks, and a 1.7 ? X-ray structure reveals its binding interactions in the ATP-binding pocket. Further investigation of the structure-activity relationship led to the development of compound 13, replacing the rhodanine-like moiety present in CVM-05-002 with an indole, a potent pan-PI5P4K inhibitor with excellent kinome-wide selectivity. Finally, we employed isothermal cellular thermal shift assays (CETSAs) to demonstrate the effective cellular target engagement of PI5P4Kα and -β by the inhibitors in HEK 293T cells.
- 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,Hall, Matthew D.,Cantley, Lewis C.,Gray, Nathanael S.
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p. 4880 - 4895
(2020/06/08)
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- 4-ARYL-1-(BIARYLMETHYLENE) PIPERIDINE COMPOUNDS
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The 4-aryl-1-(biarylmethylene)piperidine compounds are piperadine compounds having a biaryl substituent linked to the nitrogen atom of the piperidine ring by a methylene (—CH2—) group, and an aryl moiety attached to the 4-position of the piperi
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- Synthesis of new 1-Aryl-4-(biarylmethylene)piperazine ligands, structurally related to adoprazine (SLV313)
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A series of new 1-aryl-4-(biarylmethylene)piperazines has been synthesized. These ligands are structurally related to SLV-313, a potential atypical antipsychotic having potent D2 receptor antagonist and 5-HT 1A receptor agonist prope
- Ullah, Nisar
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- METHOD FOR THE PRODUCTION OF 5-ARYL NICOTINALDEHYDES
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The invention relates to a method for producing 5-aryl nicotinaldehydes by reducing the corresponding 5-aryl nicotinic acids by means of catalytic hydrogenation with a palladium complex that is stabilized with the aid of a phosphine in the presence of di-
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Page/Page column 8
(2008/06/13)
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- Heterocyclic aminoalkyl pyridine derivatives as psychopharmaceuticals
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The invention relates to heterocyclic aminoalkylpyridine derivatives of the formula I where R1 is the radical of a heterocycle having 1 to 3 ring structures, where each ring structure is saturated, unsaturated or aromatic and optionally fused t
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Page/Page column 8-9
(2008/06/13)
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- METHOD FOR THE PRODUCTION OF NICOTINALDEHYDES
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The invention relates to a method for producing nicotinaldehydes by reducing the corresponding nicotinic acid-morpholine amides.
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Page/Page column 10; 11
(2008/06/13)
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