PHARMACOLOGICAL ACTIVITY PROFILING OF PACRITINIB IN THE BIOMAP
(Abstract release date: 05/19/16)
EHA Library. Watson R. 06/09/16; 134910; PB2010
Dr. Rebecca Watson
Contributions
Contributions
Abstract
Abstract: PB2010
Type: Publication Only
Background
Pacritinib is an orally available kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. Comprehensive mapping of the pharmacological profile of pacritinib should enable a better understanding of the mechanistic basis of pharmacological action and support the utility of pacritinib in physiologically-relevant therapeutic areas.
Aims
The main goal of this study was to explore the effects of pacritinib on biomarkers relevant to human disease using BioMAP® Human Primary Cell Systems. A secondary goal was to compare and contrast the profile of pacritinib using this platform with that of other clinically available kinase inhibitors, to gauge the potential for differentiating effects of pacritinib in the clinical setting.
Methods
Pacritinib was evaluated in the BioMAP® Diversity PLUS panel by DiscoverX Corporation. Twelve human primary cell based systems were stimulated with one or more well-described biological factors to activate multiple disease-relevant signaling pathways. Each primed system was then tested with four concentrations of pacritinib ranging from 26-711 nM, encompassing physiologically and clinically relevant concentrations of the free drug (~200 nM in plasma). Anti-proliferative activity of pacritinib was determined for several human primary cell types and 148 biomarkers were measured by high-throughput immune-based assay. Biomarkers impacted by pacritinib treatment were evaluated for dose-dependency, and compared to a reference database of compounds including ruxolitinib (Jakafi), a JAK2 inhibitor approved for use in myelofibrosis.
Results
Exposure to pacritinib resulted in anti-proliferative activity in human endothelial cells, T cells, B cells, and coronary artery smooth muscle cells at 711 nM. This effect was most pronounced in B cells, the only cell type in which proliferation was also impacted at the lower, clinically relevant range. Cytotoxicity was not observed in any of the cell types. In addition, pacritinib had prominent immunomodulatory activities in the BT system modeling T-cell dependent B-cell activation. In the BT system, pacritinib resulted in statistically significant, concentration-dependent decreases in soluble TNFα, IgG, IL-17A, IL-17F, IL-2 and IL-6. Statistically significant, but less pronounced effects were also observed on inflammatory, tissue remodeling, and hemostasis-related activities. A comparison of pacritinib’s profile at 711 nM with that of 1 µM ruxolitinib in the BT system demonstrated that pacritinib had more inhibitory effects on immune biomarkers, with fewer effects on biomarkers in other systems modeling different tissue biology.
Conclusion
BioMAP® analysis indicated that pacritinib impacts several disease biomarkers in a manner that may translate to differentiated therapeutic benefit. For instance, pacritinib’s marked inhibition of inflammatory cytokines IL-17A and IL-17F and TNFα is potentially beneficial in rheumatoid arthritis, atherosclerosis, and/or psoriasis. The information obtained in the BioMAP® platform provided valuable insights that enabled selection of follow-up studies to perform in relevant animal disease models. Moreover, pacritinib’s profile was distinct from that of ruxolitinib, which may underlie some of the comparative differences observed in the clinical setting. In order to further characterize pacritinib’s effects on human disease models in comparison to other compounds, an expanded follow-on BioMAP® study is planned.
Session topic: E-poster
Keyword(s): Janus Kinase inhibitor, Myelofibrosis
Type: Publication Only
Background
Pacritinib is an orally available kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. Comprehensive mapping of the pharmacological profile of pacritinib should enable a better understanding of the mechanistic basis of pharmacological action and support the utility of pacritinib in physiologically-relevant therapeutic areas.
Aims
The main goal of this study was to explore the effects of pacritinib on biomarkers relevant to human disease using BioMAP® Human Primary Cell Systems. A secondary goal was to compare and contrast the profile of pacritinib using this platform with that of other clinically available kinase inhibitors, to gauge the potential for differentiating effects of pacritinib in the clinical setting.
Methods
Pacritinib was evaluated in the BioMAP® Diversity PLUS panel by DiscoverX Corporation. Twelve human primary cell based systems were stimulated with one or more well-described biological factors to activate multiple disease-relevant signaling pathways. Each primed system was then tested with four concentrations of pacritinib ranging from 26-711 nM, encompassing physiologically and clinically relevant concentrations of the free drug (~200 nM in plasma). Anti-proliferative activity of pacritinib was determined for several human primary cell types and 148 biomarkers were measured by high-throughput immune-based assay. Biomarkers impacted by pacritinib treatment were evaluated for dose-dependency, and compared to a reference database of compounds including ruxolitinib (Jakafi), a JAK2 inhibitor approved for use in myelofibrosis.
Results
Exposure to pacritinib resulted in anti-proliferative activity in human endothelial cells, T cells, B cells, and coronary artery smooth muscle cells at 711 nM. This effect was most pronounced in B cells, the only cell type in which proliferation was also impacted at the lower, clinically relevant range. Cytotoxicity was not observed in any of the cell types. In addition, pacritinib had prominent immunomodulatory activities in the BT system modeling T-cell dependent B-cell activation. In the BT system, pacritinib resulted in statistically significant, concentration-dependent decreases in soluble TNFα, IgG, IL-17A, IL-17F, IL-2 and IL-6. Statistically significant, but less pronounced effects were also observed on inflammatory, tissue remodeling, and hemostasis-related activities. A comparison of pacritinib’s profile at 711 nM with that of 1 µM ruxolitinib in the BT system demonstrated that pacritinib had more inhibitory effects on immune biomarkers, with fewer effects on biomarkers in other systems modeling different tissue biology.
Conclusion
BioMAP® analysis indicated that pacritinib impacts several disease biomarkers in a manner that may translate to differentiated therapeutic benefit. For instance, pacritinib’s marked inhibition of inflammatory cytokines IL-17A and IL-17F and TNFα is potentially beneficial in rheumatoid arthritis, atherosclerosis, and/or psoriasis. The information obtained in the BioMAP® platform provided valuable insights that enabled selection of follow-up studies to perform in relevant animal disease models. Moreover, pacritinib’s profile was distinct from that of ruxolitinib, which may underlie some of the comparative differences observed in the clinical setting. In order to further characterize pacritinib’s effects on human disease models in comparison to other compounds, an expanded follow-on BioMAP® study is planned.
Session topic: E-poster
Keyword(s): Janus Kinase inhibitor, Myelofibrosis
Abstract: PB2010
Type: Publication Only
Background
Pacritinib is an orally available kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. Comprehensive mapping of the pharmacological profile of pacritinib should enable a better understanding of the mechanistic basis of pharmacological action and support the utility of pacritinib in physiologically-relevant therapeutic areas.
Aims
The main goal of this study was to explore the effects of pacritinib on biomarkers relevant to human disease using BioMAP® Human Primary Cell Systems. A secondary goal was to compare and contrast the profile of pacritinib using this platform with that of other clinically available kinase inhibitors, to gauge the potential for differentiating effects of pacritinib in the clinical setting.
Methods
Pacritinib was evaluated in the BioMAP® Diversity PLUS panel by DiscoverX Corporation. Twelve human primary cell based systems were stimulated with one or more well-described biological factors to activate multiple disease-relevant signaling pathways. Each primed system was then tested with four concentrations of pacritinib ranging from 26-711 nM, encompassing physiologically and clinically relevant concentrations of the free drug (~200 nM in plasma). Anti-proliferative activity of pacritinib was determined for several human primary cell types and 148 biomarkers were measured by high-throughput immune-based assay. Biomarkers impacted by pacritinib treatment were evaluated for dose-dependency, and compared to a reference database of compounds including ruxolitinib (Jakafi), a JAK2 inhibitor approved for use in myelofibrosis.
Results
Exposure to pacritinib resulted in anti-proliferative activity in human endothelial cells, T cells, B cells, and coronary artery smooth muscle cells at 711 nM. This effect was most pronounced in B cells, the only cell type in which proliferation was also impacted at the lower, clinically relevant range. Cytotoxicity was not observed in any of the cell types. In addition, pacritinib had prominent immunomodulatory activities in the BT system modeling T-cell dependent B-cell activation. In the BT system, pacritinib resulted in statistically significant, concentration-dependent decreases in soluble TNFα, IgG, IL-17A, IL-17F, IL-2 and IL-6. Statistically significant, but less pronounced effects were also observed on inflammatory, tissue remodeling, and hemostasis-related activities. A comparison of pacritinib’s profile at 711 nM with that of 1 µM ruxolitinib in the BT system demonstrated that pacritinib had more inhibitory effects on immune biomarkers, with fewer effects on biomarkers in other systems modeling different tissue biology.
Conclusion
BioMAP® analysis indicated that pacritinib impacts several disease biomarkers in a manner that may translate to differentiated therapeutic benefit. For instance, pacritinib’s marked inhibition of inflammatory cytokines IL-17A and IL-17F and TNFα is potentially beneficial in rheumatoid arthritis, atherosclerosis, and/or psoriasis. The information obtained in the BioMAP® platform provided valuable insights that enabled selection of follow-up studies to perform in relevant animal disease models. Moreover, pacritinib’s profile was distinct from that of ruxolitinib, which may underlie some of the comparative differences observed in the clinical setting. In order to further characterize pacritinib’s effects on human disease models in comparison to other compounds, an expanded follow-on BioMAP® study is planned.
Session topic: E-poster
Keyword(s): Janus Kinase inhibitor, Myelofibrosis
Type: Publication Only
Background
Pacritinib is an orally available kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. Comprehensive mapping of the pharmacological profile of pacritinib should enable a better understanding of the mechanistic basis of pharmacological action and support the utility of pacritinib in physiologically-relevant therapeutic areas.
Aims
The main goal of this study was to explore the effects of pacritinib on biomarkers relevant to human disease using BioMAP® Human Primary Cell Systems. A secondary goal was to compare and contrast the profile of pacritinib using this platform with that of other clinically available kinase inhibitors, to gauge the potential for differentiating effects of pacritinib in the clinical setting.
Methods
Pacritinib was evaluated in the BioMAP® Diversity PLUS panel by DiscoverX Corporation. Twelve human primary cell based systems were stimulated with one or more well-described biological factors to activate multiple disease-relevant signaling pathways. Each primed system was then tested with four concentrations of pacritinib ranging from 26-711 nM, encompassing physiologically and clinically relevant concentrations of the free drug (~200 nM in plasma). Anti-proliferative activity of pacritinib was determined for several human primary cell types and 148 biomarkers were measured by high-throughput immune-based assay. Biomarkers impacted by pacritinib treatment were evaluated for dose-dependency, and compared to a reference database of compounds including ruxolitinib (Jakafi), a JAK2 inhibitor approved for use in myelofibrosis.
Results
Exposure to pacritinib resulted in anti-proliferative activity in human endothelial cells, T cells, B cells, and coronary artery smooth muscle cells at 711 nM. This effect was most pronounced in B cells, the only cell type in which proliferation was also impacted at the lower, clinically relevant range. Cytotoxicity was not observed in any of the cell types. In addition, pacritinib had prominent immunomodulatory activities in the BT system modeling T-cell dependent B-cell activation. In the BT system, pacritinib resulted in statistically significant, concentration-dependent decreases in soluble TNFα, IgG, IL-17A, IL-17F, IL-2 and IL-6. Statistically significant, but less pronounced effects were also observed on inflammatory, tissue remodeling, and hemostasis-related activities. A comparison of pacritinib’s profile at 711 nM with that of 1 µM ruxolitinib in the BT system demonstrated that pacritinib had more inhibitory effects on immune biomarkers, with fewer effects on biomarkers in other systems modeling different tissue biology.
Conclusion
BioMAP® analysis indicated that pacritinib impacts several disease biomarkers in a manner that may translate to differentiated therapeutic benefit. For instance, pacritinib’s marked inhibition of inflammatory cytokines IL-17A and IL-17F and TNFα is potentially beneficial in rheumatoid arthritis, atherosclerosis, and/or psoriasis. The information obtained in the BioMAP® platform provided valuable insights that enabled selection of follow-up studies to perform in relevant animal disease models. Moreover, pacritinib’s profile was distinct from that of ruxolitinib, which may underlie some of the comparative differences observed in the clinical setting. In order to further characterize pacritinib’s effects on human disease models in comparison to other compounds, an expanded follow-on BioMAP® study is planned.
Session topic: E-poster
Keyword(s): Janus Kinase inhibitor, Myelofibrosis
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