887973-59-3Relevant articles and documents
Discovery and structure-activity relationship study of (z)-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,Hall, Matthew D.,Cantley, Lewis C.,Gray, Nathanael S.
, p. 4880 - 4895 (2020/06/08)
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.
2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties
Charoensutthivarakul, Sitthivut,Hong, W. David,Leung, Suet C.,Gibbons, Peter D.,Bedingfield, Paul T.P.,Nixon, Gemma L.,Lawrenson, Alexandre S.,Berry, Neil G.,Ward, Stephen A.,Biagini, Giancarlo A.,O'Neill, Paul M.
supporting information, p. 1252 - 1259 (2015/07/15)
A series of 2-pyridylquinolones has been prepared in 5-7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum (Pf) has been achieved. Compared with previous analogues in this series, selected molecules h
