Abstract: Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched […]
Abstract: Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2′-deoxy-2′-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures […]
https://www.trethera.com/wp-content/uploads/2015/12/trethera_logo-wo.png00Tretherahttps://www.trethera.com/wp-content/uploads/2015/12/trethera_logo-wo.pngTrethera2021-03-05 03:57:462021-03-08 17:48:3418 F-FAC PET Visualizes Brain-Infiltrating Leukocytes in a Mouse Model of Multiple Sclerosis
Abstract: Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated […]
https://www.trethera.com/wp-content/uploads/2015/12/trethera_logo-wo.png00adminhttps://www.trethera.com/wp-content/uploads/2015/12/trethera_logo-wo.pngadmin2014-11-26 12:07:382017-03-06 12:10:05Structure-Guided Development of Deoxycytidine Kinase Inhibitors with Nanomolar Affinity and Improved Metabolic Stability
Abstract: Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts […]
https://www.trethera.com/wp-content/uploads/2015/12/trethera_logo-wo.png00adminhttps://www.trethera.com/wp-content/uploads/2015/12/trethera_logo-wo.pngadmin2014-08-07 12:10:262017-03-06 12:11:07Deoxycytidine Kinase Augments ATM-Mediated DNA Repair and Contributes to Radiation Resistance
Abstract: Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show […]
Targeting Deoxycytidine Kinase Improves Symptoms in Mouse Models of Multiple Sclerosis
/in Publications /by TretheraAbstract: Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched […]
18 F-FAC PET Visualizes Brain-Infiltrating Leukocytes in a Mouse Model of Multiple Sclerosis
/in Publications /by TretheraAbstract: Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2′-deoxy-2′-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures […]
Structure-Guided Development of Deoxycytidine Kinase Inhibitors with Nanomolar Affinity and Improved Metabolic Stability
/in Publications /by adminAbstract: Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated […]
Deoxycytidine Kinase Augments ATM-Mediated DNA Repair and Contributes to Radiation Resistance
/in Publications /by adminAbstract: Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts […]
Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress
/in Publications /by adminAbstract: Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show […]