neil wishart | The University of Newcastle (original) (raw)
Papers by neil wishart
Archives of biochemistry and biophysics, 2005
Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of th... more Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of the Erk MAPK cascade in macrophages. COT 30--467 is insoluble, whereas low levels of COT 30--397 can be expressed, but this protein is unstable. However, both COT 30--467 and COT 30--397 are expressed in a soluble and stable form when produced in complex with the C-terminal half of p105. The k(cat) of COT 30--397 is reduced approximately 47--fold in the COT 30--467/p105 Delta N complex. COT prefers Mn(2+) to Mg(2+) as the ATP metal cofactor, exhibiting an unusually high ATP K(m) in the presence of Mg(2+). When using Mn(2+) as the cofactor, the ATP K(m) is reduced to a level typical of most kinases. In contrast, the binding affinity of COT for its other substrate MEK is cofactor independent. Our results using purified proteins indicate that p105 binding improves COT solubility and stability while down-regulating kinase activity, consistent with cellular data showing that p105 functions as a...
La presente invention porte sur de nouveaux composes de la formule (I), sur des sels, des promedi... more La presente invention porte sur de nouveaux composes de la formule (I), sur des sels, des promedicaments, des metabolites biologiquement actifs, des stereo-isomeres et des isomeres de qualite pharmaceutique de ceux-ci, dans ladite formule les variables etant tels que definies dans la description. Les composes de la formule (I) sont utiles en tant qu'inhibiteurs de kinases et en tant que tels seraient utiles dans le traitement de certaines affections et maladies, en particulier d'affections et de maladies inflammatoires, et de troubles et d'affections proliferatifs, par exemple la polyarthrite rhumatoide, le lupus erythemateux dissemine, la sclerose en plaques, la maladie de Crohn, le psoriasis et l'asthme.
BMC Rheumatology
Background: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK i... more Background: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods: Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results: Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is~60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions: The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.
Arthritis & rheumatology (Hoboken, N.J.), Jan 31, 2018
This study investigated the safety and efficacy of ABT-122, a TNF- and IL-17A-targeted dual varia... more This study investigated the safety and efficacy of ABT-122, a TNF- and IL-17A-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) with an inadequate response to methotrexate. Patients (N=240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week, double-blind, parallel-group study (NCT02349451). The primary efficacy endpoint was ≥20% improvement in American College of Rheumatology criteria (ACR20 response) at week 12. Secondary and exploratory 12-week endpoints included ACR50, ACR70, and Psoriasis Area and Severity Index (PASI75 and PASI90 skin scores) in patients with ≥3% body surface affected. For both ABT-122 dose groups, ACR20 responses at week 12 (64.8% to 75.3%) were superior to placebo (25.0%; P<0.001) but not adalimumab (68.1%). ACR50 and ACR70 responses were also superior for both ABT-122 dose groups (36.6% to 53.4% and 22.5% to 31.5%, respectively) versus pl...
Toxicologic pathology, Oct 19, 2016
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzy... more Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusio...
Archives of biochemistry and biophysics, 2005
Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of th... more Cancer osaka thyroid (COT), a human MAP 3 K, is essential for lipopolysaccharide activation of the Erk MAPK cascade in macrophages. COT 30--467 is insoluble, whereas low levels of COT 30--397 can be expressed, but this protein is unstable. However, both COT 30--467 and COT 30--397 are expressed in a soluble and stable form when produced in complex with the C-terminal half of p105. The k(cat) of COT 30--397 is reduced approximately 47--fold in the COT 30--467/p105 Delta N complex. COT prefers Mn(2+) to Mg(2+) as the ATP metal cofactor, exhibiting an unusually high ATP K(m) in the presence of Mg(2+). When using Mn(2+) as the cofactor, the ATP K(m) is reduced to a level typical of most kinases. In contrast, the binding affinity of COT for its other substrate MEK is cofactor independent. Our results using purified proteins indicate that p105 binding improves COT solubility and stability while down-regulating kinase activity, consistent with cellular data showing that p105 functions as a...
La presente invention porte sur de nouveaux composes de la formule (I), sur des sels, des promedi... more La presente invention porte sur de nouveaux composes de la formule (I), sur des sels, des promedicaments, des metabolites biologiquement actifs, des stereo-isomeres et des isomeres de qualite pharmaceutique de ceux-ci, dans ladite formule les variables etant tels que definies dans la description. Les composes de la formule (I) sont utiles en tant qu'inhibiteurs de kinases et en tant que tels seraient utiles dans le traitement de certaines affections et maladies, en particulier d'affections et de maladies inflammatoires, et de troubles et d'affections proliferatifs, par exemple la polyarthrite rhumatoide, le lupus erythemateux dissemine, la sclerose en plaques, la maladie de Crohn, le psoriasis et l'asthme.
BMC Rheumatology
Background: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK i... more Background: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods: Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results: Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is~60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions: The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.
Arthritis & rheumatology (Hoboken, N.J.), Jan 31, 2018
This study investigated the safety and efficacy of ABT-122, a TNF- and IL-17A-targeted dual varia... more This study investigated the safety and efficacy of ABT-122, a TNF- and IL-17A-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) with an inadequate response to methotrexate. Patients (N=240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week, double-blind, parallel-group study (NCT02349451). The primary efficacy endpoint was ≥20% improvement in American College of Rheumatology criteria (ACR20 response) at week 12. Secondary and exploratory 12-week endpoints included ACR50, ACR70, and Psoriasis Area and Severity Index (PASI75 and PASI90 skin scores) in patients with ≥3% body surface affected. For both ABT-122 dose groups, ACR20 responses at week 12 (64.8% to 75.3%) were superior to placebo (25.0%; P<0.001) but not adalimumab (68.1%). ACR50 and ACR70 responses were also superior for both ABT-122 dose groups (36.6% to 53.4% and 22.5% to 31.5%, respectively) versus pl...
Toxicologic pathology, Oct 19, 2016
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzy... more Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusio...