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Chemical Interrogation of FOXO3a Nuclear Translocation Identifies Potent and Selective Inhibitors of Phosphoinositide 3-Kinases*
A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold that leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice. Expand
Structure, physiological role, and specific inhibitors of human thymidine kinase 2 (TK2): Present and future
TK2 inhibitors can be considered as valuable tools to unravel the role of TK2 in the maintenance and homeostasis of mitochondrial nucleotide pools and mtDNA, and to clarify the contribution of Tk2 activity to mitochondrial toxicity of certain antivirals. Expand
Thymidine phosphorylase inhibitors: recent developments and potential therapeutic applications.
The most recent approaches in the search for novel TPase inhibitors together with the potential therapeutic applications of such inhibitors are summarized. Expand
The Nucleoside Derivative 5′-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action*
The inhibitory activity of the purine riboside derivative KIN59 (5′-O-tritylinosine) against human and bacterial recombinant TPase and TPase-induced angiogenesis indicates that the angiogenic activity of TPase is not solely directed through its functional nucleoside and phosphate-binding sites. Expand
5′-O-Tritylated Nucleoside Derivatives: Inhibition of Thymidine Phosphorylase and Angiogenesis
A variety of novel 5′-O-trityl nucleoside derivatives combine antiangiogenic and vascular-targeting activities, which opens perspectives for their potential use as anticancer agents. Expand
5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase.
On the basis of our previous findings that 5'-O-tritylinosine (KIN59) behaves as an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase (TPase), we have undertaken the synthesis andExpand
Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase
The discovery of the first acyclic nucleoside analogues that potently and selectively inhibit TMPKmt, and the fact that these inhibitors are more easily synthesizable than previously identified T MPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization. Expand
Bromovinyl-deoxyuridine: A selective substrate for mitochondrial thymidine kinase in cell extracts.
The value of the thymidine analog (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) as a TK2-specific substrate was tested and it was shown that BVDU, but not 1-(beta-d-arabinofuranosyl)thymine (Ara-T), discriminates TK 2 activity even in the presence of 100-fold excess TK1. Expand
Non-nucleoside inhibitors of mitochondrial thymidine kinase (TK-2) differentially inhibit the closely related herpes simplex virus type 1 TK and Drosophila melanogaster multifunctional
KIN-12, and particularly KIN-52, are the very first non-nucleoside specific inhibitors of TK-2 reported and may be useful for studying the physiological role of the mitochondrial Tk-2 enzyme. Expand
Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor.
The optimization of imidazo [1,2-a] pyrazines is described, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. Expand