The Experts below are selected from a list of 150579 Experts worldwide ranked by ideXlab platform
Jinhai Wang - One of the best experts on this subject based on the ideXlab platform.
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abstract 4541 utilization of k48 poly ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic preclinical validation with cb 5083 a first in class inhibitor of the aaa atpase p97
Cancer Research, 2016Co-Authors: Marykamala Menon, Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Ferdie Soriano, W U Tony, Jinhai WangAbstract:Background: Pharmacodynamic (PD) biomarkers are an increasingly valuable tool for decision-making and prioritization of lead compounds during preclinical and clinical studies as they link drug-target inhibition in cells with biological activity. They are of particular importance for novel, first-in-class mechanisms, where the ability of a targeted therapeutic to impact disease outcome is unknown. We recently discovered CB-5083, a novel small molecule inhibitor of p97, a Protein involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. Accumulation of K48 poly-ubiquitinated Proteins is a hallmark of Protein degradation inhibition, and we used this proximal biomarker to follow CB-5083 target engagement on p97 in various pre-clinical models. Results: CB-5083 is a potent inhibitor of p97, with a biochemical IC50 of 11 nM. When cancer cells are exposed to CB-5083, biological consequences linked to p97 inhibition are detected, including ERAD inhibition, ER (endoplasmic reticulum) stress, ER stress-mediated cell death and accumulation of poly-ubiquitinated Proteins. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of K48 poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in K48 poly-ubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Accumulation of K48 poly-ubiquitin also occurs in other tissues in the body and we developed a quantitative method to detect accumulation of K48 poly-ubiquitin as a marker of target engagement in whole blood. With this method, we were able to compare the kinetics and level of K48 poly ubiquitin accumulation following CB-5083 administration in both tumor and whole blood. We also performed a dose escalation of CB-5083 in cynomolgus monkeys and defined the minimal plasma AUC and Cmax required to see accumulation of K48 poly-ubiquitin in monkey whole blood. This approach allowed us to predict human exposures that should lead to target engagement and consequent biological activity in our ongoing phase 1 studies where a flow cytometry based assay is being used to monitor K48 poly-ubiquitin levels in patient blood samples. Conclusion: K48 poly-ubiquitin is a target engagement biomarker of p97 inhibition. CB-5083, a p97 inhibitor, can induce sustained induction of K48 poly-ubiquitin, not only in tumor but also in surrogate tissues such as whole blood. K48 poly-ubiquitin accumulation is currently being assessed to follow target engagement in the blood of patients in our ongoing phase 1 dose escalation studies of CB-5083. Citation Format: Mary-Kamala MENON, Ferdie SORIANO, Steve WONG, Eduardo VALLE, Stevan Djakovic, Brajesh KUMAR, Bing YAO, Antonett MADRIAGA, Tony WU, Julie RICE, Jinhai WANG, Alessandra CESANO, Laura SHAWVER, Han-Jie ZHOU, David WUSTROW, Daniel ANDERSON, Mark ROLFE, Ronan LE MOIGNE. Utilization of K48 poly-ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic: Preclinical validation with CB-5083, a first-in-class inhibitor of the AAA ATPase p97. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4541.
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targeting the aaa atpase p97 as an approach to treat cancer through disruption of Protein Homeostasis
Cancer Cell, 2015Co-Authors: Daniel J Anderson, Brajesh Kumar, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Jinhai Wang, Ronan Le Moigne, Bing Yao, Szerenke Kiss Von SolyAbstract:p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of Protein Homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated Proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded Protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.
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cb 5083 a p97 inhibitor disrupts cellular Protein Homeostasis and shows potent anti tumor effects
The FASEB Journal, 2015Co-Authors: Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Mk Menon, Jinhai Wang, Szerenke Kiss Von Soly, Ferdie SorianoAbstract:p97 is a homo-hexameric AAA-ATPase complex that plays vital roles in Protein Homeostasis, including ubiquitin-proteasome mediated Protein degradation, endoplasmic reticulum-associated degradation (...
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abstract 951 cb 5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti tumor activity in solid and hematological models
Cancer Research, 2014Co-Authors: Ronan Le Moigne, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Ferdie Soriano, Daniel J Anderson, Bing Yao, Marykamala Menon, Jinhai WangAbstract:Background: The AAA-ATPase p97/VCP facilitates the extraction and degradation of ubiquitinated Proteins by converting chemical energy into mechanical force. p97 is closely involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. p97 has been increasingly linked to cancer: it showed elevated Protein expression in tumors, it can mediate the degradation of Proteins in cancer-relevant pathways and is required for orchestrating the ubiquitin-governed DNA-damage response. In this context, p97 inhibitors may have an advantage versus other Protein Homeostasis inhibitors and may be active in solid tumors where 26S proteasome inhibitors, bortezomib and carfilzomib, have shown poor efficacy. We report here p97 inhibition as a novel approach to exploit cancer cell addiction to Protein homeostatic mechanisms. Results: We have discovered novel small molecule inhibitors of p97 ATPase activity with nanomolar enzymatic and cellular potency. In cellular models, treatment of cancer cells with our lead compound CB-5083 causes disruptions in specific p97 functions, including ubiquitin-dependent Protein degradation, ERAD, endocytosis and autophagy. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in polyubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Sub-chronic oral administration of CB-5083 is generally well-tolerated with 50% reduction in M-spike. Additional efforts are focused on the development of translational assays to monitor p97 target engagement and antitumor efficacy in upcoming clinical trials of CB-5083. Conclusion: These data demonstrate that CB-5083 is a potent inhibitor of p97 that translates to tumor growth inhibition in multiple rodent models of human cancer. Furthermore, CB-5083 appears to exhibit greater potency over current proteasome inhibitors that further validate targeting p97 and Protein Homeostasis in the treatment of cancer. Citation Format: Ronan Le Moigne, Steve Wong, Ferdie Soriano, Eduardo Valle, Daniel J. Anderson, Stevan Djakovic, Mary-Kamala Menon, Bing Yao, Julie Rice, Jinhai Wang, Szerenke Kiss Von Soly, Brajesh Kumar, Marta Chesi, P. Leif Bergsagel, Han-Jie Zhou, David Wustrow, Mark Rolfe, F. Michael Yakes. CB-5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti-tumor activity in solid and hematological models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 951. doi:10.1158/1538-7445.AM2014-951
Manuel Rodriguezconcepcion - One of the best experts on this subject based on the ideXlab platform.
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interference with plastome gene expression and clp protease activity in arabidopsis triggers a chloroplast unfolded Protein response to restore Protein Homeostasis
PLOS Genetics, 2017Co-Authors: Ernesto Llamas, Pablo Pulido, Manuel RodriguezconcepcionAbstract:Disruption of Protein Homeostasis in chloroplasts impairs the correct functioning of essential metabolic pathways, including the methylerythritol 4-phosphate (MEP) pathway for the production of plastidial isoprenoids involved in photosynthesis and growth. We previously found that misfolded and aggregated forms of the first enzyme of the MEP pathway are degraded by the Clp protease with the involvement of Hsp70 and Hsp100/ClpC1 chaperones in Arabidopsis thaliana. By contrast, the combined unfolding and disaggregating actions of Hsp70 and Hsp100/ClpB3 chaperones allow solubilization and hence reactivation of the enzyme. The repair pathway is promoted when the levels of ClpB3 Proteins increase upon reduction of Clp protease activity in mutants or wild-type plants treated with the chloroplast Protein synthesis inhibitor lincomycin (LIN). Here we show that LIN treatment rapidly increases the levels of aggregated Proteins in the chloroplast, unleashing a specific retrograde signaling pathway that up-regulates expression of ClpB3 and other nuclear genes encoding plastidial chaperones. As a consequence, folding capacity is increased to restore Protein Homeostasis. This sort of chloroplast unfolded Protein response (cpUPR) mechanism appears to be mediated by the heat shock transcription factor HsfA2. Expression of HsfA2 and cpUPR-related target genes is independent of GUN1, a central integrator of retrograde signaling pathways. However, double mutants defective in both GUN1 and plastome gene expression (or Clp protease activity) are seedling lethal, confirming that the GUN1 Protein is essential for Protein Homeostasis in chloroplasts.
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interference with plastome gene expression and clp protease activity in arabidopsis triggers a chloroplast unfolded Protein response to restore Protein Homeostasis
PLOS Genetics, 2017Co-Authors: Ernesto Llamas, Pablo Pulido, Manuel RodriguezconcepcionAbstract:Disruption of Protein Homeostasis in chloroplasts impairs the correct functioning of essential metabolic pathways, including the methylerythritol 4-phosphate (MEP) pathway for the production of plastidial isoprenoids involved in photosynthesis and growth. We previously found that misfolded and aggregated forms of the first enzyme of the MEP pathway are degraded by the Clp protease with the involvement of Hsp70 and Hsp100/ClpC1 chaperones in Arabidopsis thaliana. By contrast, the combined unfolding and disaggregating actions of Hsp70 and Hsp100/ClpB3 chaperones allow solubilization and hence reactivation of the enzyme. The repair pathway is promoted when the levels of ClpB3 Proteins increase upon reduction of Clp protease activity in mutants or wild-type plants treated with the chloroplast Protein synthesis inhibitor lincomycin (LIN). Here we show that LIN treatment rapidly increases the levels of aggregated Proteins in the chloroplast, unleashing a specific retrograde signaling pathway that up-regulates expression of ClpB3 and other nuclear genes encoding plastidial chaperones. As a consequence, folding capacity is increased to restore Protein Homeostasis. This sort of chloroplast unfolded Protein response (cpUPR) mechanism appears to be mediated by the heat shock transcription factor HsfA2. Expression of HsfA2 and cpUPR-related target genes is independent of GUN1, a central integrator of retrograde signaling pathways. However, double mutants defective in both GUN1 and plastome gene expression (or Clp protease activity) are seedling lethal, confirming that the GUN1 Protein is essential for Protein Homeostasis in chloroplasts.
Steve Wong - One of the best experts on this subject based on the ideXlab platform.
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abstract 4541 utilization of k48 poly ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic preclinical validation with cb 5083 a first in class inhibitor of the aaa atpase p97
Cancer Research, 2016Co-Authors: Marykamala Menon, Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Ferdie Soriano, W U Tony, Jinhai WangAbstract:Background: Pharmacodynamic (PD) biomarkers are an increasingly valuable tool for decision-making and prioritization of lead compounds during preclinical and clinical studies as they link drug-target inhibition in cells with biological activity. They are of particular importance for novel, first-in-class mechanisms, where the ability of a targeted therapeutic to impact disease outcome is unknown. We recently discovered CB-5083, a novel small molecule inhibitor of p97, a Protein involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. Accumulation of K48 poly-ubiquitinated Proteins is a hallmark of Protein degradation inhibition, and we used this proximal biomarker to follow CB-5083 target engagement on p97 in various pre-clinical models. Results: CB-5083 is a potent inhibitor of p97, with a biochemical IC50 of 11 nM. When cancer cells are exposed to CB-5083, biological consequences linked to p97 inhibition are detected, including ERAD inhibition, ER (endoplasmic reticulum) stress, ER stress-mediated cell death and accumulation of poly-ubiquitinated Proteins. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of K48 poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in K48 poly-ubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Accumulation of K48 poly-ubiquitin also occurs in other tissues in the body and we developed a quantitative method to detect accumulation of K48 poly-ubiquitin as a marker of target engagement in whole blood. With this method, we were able to compare the kinetics and level of K48 poly ubiquitin accumulation following CB-5083 administration in both tumor and whole blood. We also performed a dose escalation of CB-5083 in cynomolgus monkeys and defined the minimal plasma AUC and Cmax required to see accumulation of K48 poly-ubiquitin in monkey whole blood. This approach allowed us to predict human exposures that should lead to target engagement and consequent biological activity in our ongoing phase 1 studies where a flow cytometry based assay is being used to monitor K48 poly-ubiquitin levels in patient blood samples. Conclusion: K48 poly-ubiquitin is a target engagement biomarker of p97 inhibition. CB-5083, a p97 inhibitor, can induce sustained induction of K48 poly-ubiquitin, not only in tumor but also in surrogate tissues such as whole blood. K48 poly-ubiquitin accumulation is currently being assessed to follow target engagement in the blood of patients in our ongoing phase 1 dose escalation studies of CB-5083. Citation Format: Mary-Kamala MENON, Ferdie SORIANO, Steve WONG, Eduardo VALLE, Stevan Djakovic, Brajesh KUMAR, Bing YAO, Antonett MADRIAGA, Tony WU, Julie RICE, Jinhai WANG, Alessandra CESANO, Laura SHAWVER, Han-Jie ZHOU, David WUSTROW, Daniel ANDERSON, Mark ROLFE, Ronan LE MOIGNE. Utilization of K48 poly-ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic: Preclinical validation with CB-5083, a first-in-class inhibitor of the AAA ATPase p97. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4541.
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targeting the aaa atpase p97 as an approach to treat cancer through disruption of Protein Homeostasis
Cancer Cell, 2015Co-Authors: Daniel J Anderson, Brajesh Kumar, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Jinhai Wang, Ronan Le Moigne, Bing Yao, Szerenke Kiss Von SolyAbstract:p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of Protein Homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated Proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded Protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.
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cb 5083 a p97 inhibitor disrupts cellular Protein Homeostasis and shows potent anti tumor effects
The FASEB Journal, 2015Co-Authors: Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Mk Menon, Jinhai Wang, Szerenke Kiss Von Soly, Ferdie SorianoAbstract:p97 is a homo-hexameric AAA-ATPase complex that plays vital roles in Protein Homeostasis, including ubiquitin-proteasome mediated Protein degradation, endoplasmic reticulum-associated degradation (...
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abstract 951 cb 5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti tumor activity in solid and hematological models
Cancer Research, 2014Co-Authors: Ronan Le Moigne, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Ferdie Soriano, Daniel J Anderson, Bing Yao, Marykamala Menon, Jinhai WangAbstract:Background: The AAA-ATPase p97/VCP facilitates the extraction and degradation of ubiquitinated Proteins by converting chemical energy into mechanical force. p97 is closely involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. p97 has been increasingly linked to cancer: it showed elevated Protein expression in tumors, it can mediate the degradation of Proteins in cancer-relevant pathways and is required for orchestrating the ubiquitin-governed DNA-damage response. In this context, p97 inhibitors may have an advantage versus other Protein Homeostasis inhibitors and may be active in solid tumors where 26S proteasome inhibitors, bortezomib and carfilzomib, have shown poor efficacy. We report here p97 inhibition as a novel approach to exploit cancer cell addiction to Protein homeostatic mechanisms. Results: We have discovered novel small molecule inhibitors of p97 ATPase activity with nanomolar enzymatic and cellular potency. In cellular models, treatment of cancer cells with our lead compound CB-5083 causes disruptions in specific p97 functions, including ubiquitin-dependent Protein degradation, ERAD, endocytosis and autophagy. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in polyubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Sub-chronic oral administration of CB-5083 is generally well-tolerated with 50% reduction in M-spike. Additional efforts are focused on the development of translational assays to monitor p97 target engagement and antitumor efficacy in upcoming clinical trials of CB-5083. Conclusion: These data demonstrate that CB-5083 is a potent inhibitor of p97 that translates to tumor growth inhibition in multiple rodent models of human cancer. Furthermore, CB-5083 appears to exhibit greater potency over current proteasome inhibitors that further validate targeting p97 and Protein Homeostasis in the treatment of cancer. Citation Format: Ronan Le Moigne, Steve Wong, Ferdie Soriano, Eduardo Valle, Daniel J. Anderson, Stevan Djakovic, Mary-Kamala Menon, Bing Yao, Julie Rice, Jinhai Wang, Szerenke Kiss Von Soly, Brajesh Kumar, Marta Chesi, P. Leif Bergsagel, Han-Jie Zhou, David Wustrow, Mark Rolfe, F. Michael Yakes. CB-5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti-tumor activity in solid and hematological models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 951. doi:10.1158/1538-7445.AM2014-951
Stevan Djakovic - One of the best experts on this subject based on the ideXlab platform.
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abstract 4541 utilization of k48 poly ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic preclinical validation with cb 5083 a first in class inhibitor of the aaa atpase p97
Cancer Research, 2016Co-Authors: Marykamala Menon, Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Ferdie Soriano, W U Tony, Jinhai WangAbstract:Background: Pharmacodynamic (PD) biomarkers are an increasingly valuable tool for decision-making and prioritization of lead compounds during preclinical and clinical studies as they link drug-target inhibition in cells with biological activity. They are of particular importance for novel, first-in-class mechanisms, where the ability of a targeted therapeutic to impact disease outcome is unknown. We recently discovered CB-5083, a novel small molecule inhibitor of p97, a Protein involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. Accumulation of K48 poly-ubiquitinated Proteins is a hallmark of Protein degradation inhibition, and we used this proximal biomarker to follow CB-5083 target engagement on p97 in various pre-clinical models. Results: CB-5083 is a potent inhibitor of p97, with a biochemical IC50 of 11 nM. When cancer cells are exposed to CB-5083, biological consequences linked to p97 inhibition are detected, including ERAD inhibition, ER (endoplasmic reticulum) stress, ER stress-mediated cell death and accumulation of poly-ubiquitinated Proteins. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of K48 poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in K48 poly-ubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Accumulation of K48 poly-ubiquitin also occurs in other tissues in the body and we developed a quantitative method to detect accumulation of K48 poly-ubiquitin as a marker of target engagement in whole blood. With this method, we were able to compare the kinetics and level of K48 poly ubiquitin accumulation following CB-5083 administration in both tumor and whole blood. We also performed a dose escalation of CB-5083 in cynomolgus monkeys and defined the minimal plasma AUC and Cmax required to see accumulation of K48 poly-ubiquitin in monkey whole blood. This approach allowed us to predict human exposures that should lead to target engagement and consequent biological activity in our ongoing phase 1 studies where a flow cytometry based assay is being used to monitor K48 poly-ubiquitin levels in patient blood samples. Conclusion: K48 poly-ubiquitin is a target engagement biomarker of p97 inhibition. CB-5083, a p97 inhibitor, can induce sustained induction of K48 poly-ubiquitin, not only in tumor but also in surrogate tissues such as whole blood. K48 poly-ubiquitin accumulation is currently being assessed to follow target engagement in the blood of patients in our ongoing phase 1 dose escalation studies of CB-5083. Citation Format: Mary-Kamala MENON, Ferdie SORIANO, Steve WONG, Eduardo VALLE, Stevan Djakovic, Brajesh KUMAR, Bing YAO, Antonett MADRIAGA, Tony WU, Julie RICE, Jinhai WANG, Alessandra CESANO, Laura SHAWVER, Han-Jie ZHOU, David WUSTROW, Daniel ANDERSON, Mark ROLFE, Ronan LE MOIGNE. Utilization of K48 poly-ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic: Preclinical validation with CB-5083, a first-in-class inhibitor of the AAA ATPase p97. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4541.
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targeting the aaa atpase p97 as an approach to treat cancer through disruption of Protein Homeostasis
Cancer Cell, 2015Co-Authors: Daniel J Anderson, Brajesh Kumar, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Jinhai Wang, Ronan Le Moigne, Bing Yao, Szerenke Kiss Von SolyAbstract:p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of Protein Homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated Proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded Protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.
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cb 5083 a p97 inhibitor disrupts cellular Protein Homeostasis and shows potent anti tumor effects
The FASEB Journal, 2015Co-Authors: Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Mk Menon, Jinhai Wang, Szerenke Kiss Von Soly, Ferdie SorianoAbstract:p97 is a homo-hexameric AAA-ATPase complex that plays vital roles in Protein Homeostasis, including ubiquitin-proteasome mediated Protein degradation, endoplasmic reticulum-associated degradation (...
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abstract 951 cb 5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti tumor activity in solid and hematological models
Cancer Research, 2014Co-Authors: Ronan Le Moigne, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Ferdie Soriano, Daniel J Anderson, Bing Yao, Marykamala Menon, Jinhai WangAbstract:Background: The AAA-ATPase p97/VCP facilitates the extraction and degradation of ubiquitinated Proteins by converting chemical energy into mechanical force. p97 is closely involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. p97 has been increasingly linked to cancer: it showed elevated Protein expression in tumors, it can mediate the degradation of Proteins in cancer-relevant pathways and is required for orchestrating the ubiquitin-governed DNA-damage response. In this context, p97 inhibitors may have an advantage versus other Protein Homeostasis inhibitors and may be active in solid tumors where 26S proteasome inhibitors, bortezomib and carfilzomib, have shown poor efficacy. We report here p97 inhibition as a novel approach to exploit cancer cell addiction to Protein homeostatic mechanisms. Results: We have discovered novel small molecule inhibitors of p97 ATPase activity with nanomolar enzymatic and cellular potency. In cellular models, treatment of cancer cells with our lead compound CB-5083 causes disruptions in specific p97 functions, including ubiquitin-dependent Protein degradation, ERAD, endocytosis and autophagy. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in polyubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Sub-chronic oral administration of CB-5083 is generally well-tolerated with 50% reduction in M-spike. Additional efforts are focused on the development of translational assays to monitor p97 target engagement and antitumor efficacy in upcoming clinical trials of CB-5083. Conclusion: These data demonstrate that CB-5083 is a potent inhibitor of p97 that translates to tumor growth inhibition in multiple rodent models of human cancer. Furthermore, CB-5083 appears to exhibit greater potency over current proteasome inhibitors that further validate targeting p97 and Protein Homeostasis in the treatment of cancer. Citation Format: Ronan Le Moigne, Steve Wong, Ferdie Soriano, Eduardo Valle, Daniel J. Anderson, Stevan Djakovic, Mary-Kamala Menon, Bing Yao, Julie Rice, Jinhai Wang, Szerenke Kiss Von Soly, Brajesh Kumar, Marta Chesi, P. Leif Bergsagel, Han-Jie Zhou, David Wustrow, Mark Rolfe, F. Michael Yakes. CB-5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti-tumor activity in solid and hematological models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 951. doi:10.1158/1538-7445.AM2014-951
Julie Rice - One of the best experts on this subject based on the ideXlab platform.
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abstract 4541 utilization of k48 poly ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic preclinical validation with cb 5083 a first in class inhibitor of the aaa atpase p97
Cancer Research, 2016Co-Authors: Marykamala Menon, Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Ferdie Soriano, W U Tony, Jinhai WangAbstract:Background: Pharmacodynamic (PD) biomarkers are an increasingly valuable tool for decision-making and prioritization of lead compounds during preclinical and clinical studies as they link drug-target inhibition in cells with biological activity. They are of particular importance for novel, first-in-class mechanisms, where the ability of a targeted therapeutic to impact disease outcome is unknown. We recently discovered CB-5083, a novel small molecule inhibitor of p97, a Protein involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. Accumulation of K48 poly-ubiquitinated Proteins is a hallmark of Protein degradation inhibition, and we used this proximal biomarker to follow CB-5083 target engagement on p97 in various pre-clinical models. Results: CB-5083 is a potent inhibitor of p97, with a biochemical IC50 of 11 nM. When cancer cells are exposed to CB-5083, biological consequences linked to p97 inhibition are detected, including ERAD inhibition, ER (endoplasmic reticulum) stress, ER stress-mediated cell death and accumulation of poly-ubiquitinated Proteins. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of K48 poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in K48 poly-ubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Accumulation of K48 poly-ubiquitin also occurs in other tissues in the body and we developed a quantitative method to detect accumulation of K48 poly-ubiquitin as a marker of target engagement in whole blood. With this method, we were able to compare the kinetics and level of K48 poly ubiquitin accumulation following CB-5083 administration in both tumor and whole blood. We also performed a dose escalation of CB-5083 in cynomolgus monkeys and defined the minimal plasma AUC and Cmax required to see accumulation of K48 poly-ubiquitin in monkey whole blood. This approach allowed us to predict human exposures that should lead to target engagement and consequent biological activity in our ongoing phase 1 studies where a flow cytometry based assay is being used to monitor K48 poly-ubiquitin levels in patient blood samples. Conclusion: K48 poly-ubiquitin is a target engagement biomarker of p97 inhibition. CB-5083, a p97 inhibitor, can induce sustained induction of K48 poly-ubiquitin, not only in tumor but also in surrogate tissues such as whole blood. K48 poly-ubiquitin accumulation is currently being assessed to follow target engagement in the blood of patients in our ongoing phase 1 dose escalation studies of CB-5083. Citation Format: Mary-Kamala MENON, Ferdie SORIANO, Steve WONG, Eduardo VALLE, Stevan Djakovic, Brajesh KUMAR, Bing YAO, Antonett MADRIAGA, Tony WU, Julie RICE, Jinhai WANG, Alessandra CESANO, Laura SHAWVER, Han-Jie ZHOU, David WUSTROW, Daniel ANDERSON, Mark ROLFE, Ronan LE MOIGNE. Utilization of K48 poly-ubiquitin modulation as a biomarker of target engagement for a Protein Homeostasis inhibitor in the clinic: Preclinical validation with CB-5083, a first-in-class inhibitor of the AAA ATPase p97. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4541.
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targeting the aaa atpase p97 as an approach to treat cancer through disruption of Protein Homeostasis
Cancer Cell, 2015Co-Authors: Daniel J Anderson, Brajesh Kumar, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Jinhai Wang, Ronan Le Moigne, Bing Yao, Szerenke Kiss Von SolyAbstract:p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of Protein Homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated Proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded Protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection.
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cb 5083 a p97 inhibitor disrupts cellular Protein Homeostasis and shows potent anti tumor effects
The FASEB Journal, 2015Co-Authors: Brajesh Kumar, Julie Rice, Stevan Djakovic, Antonett Madriaga, Steve Wong, Eduardo Valle, Mk Menon, Jinhai Wang, Szerenke Kiss Von Soly, Ferdie SorianoAbstract:p97 is a homo-hexameric AAA-ATPase complex that plays vital roles in Protein Homeostasis, including ubiquitin-proteasome mediated Protein degradation, endoplasmic reticulum-associated degradation (...
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abstract 951 cb 5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti tumor activity in solid and hematological models
Cancer Research, 2014Co-Authors: Ronan Le Moigne, Julie Rice, Stevan Djakovic, Steve Wong, Eduardo Valle, Ferdie Soriano, Daniel J Anderson, Bing Yao, Marykamala Menon, Jinhai WangAbstract:Background: The AAA-ATPase p97/VCP facilitates the extraction and degradation of ubiquitinated Proteins by converting chemical energy into mechanical force. p97 is closely involved in several facets of Protein Homeostasis, including ubiquitin-dependent Protein degradation, endoplasmic reticulum-associated degradation (ERAD) and autophagy. p97 has been increasingly linked to cancer: it showed elevated Protein expression in tumors, it can mediate the degradation of Proteins in cancer-relevant pathways and is required for orchestrating the ubiquitin-governed DNA-damage response. In this context, p97 inhibitors may have an advantage versus other Protein Homeostasis inhibitors and may be active in solid tumors where 26S proteasome inhibitors, bortezomib and carfilzomib, have shown poor efficacy. We report here p97 inhibition as a novel approach to exploit cancer cell addiction to Protein homeostatic mechanisms. Results: We have discovered novel small molecule inhibitors of p97 ATPase activity with nanomolar enzymatic and cellular potency. In cellular models, treatment of cancer cells with our lead compound CB-5083 causes disruptions in specific p97 functions, including ubiquitin-dependent Protein degradation, ERAD, endocytosis and autophagy. In mouse models, CB-5083 is orally bio-available and causes rapid and sustained accumulation of poly-ubiquitin in tumor xenografts after a single administration. Concurrent with increases in polyubiquitin levels, activation of ER stress response pathways and induction of apoptosis markers are also observed. Sub-chronic oral administration of CB-5083 is generally well-tolerated with 50% reduction in M-spike. Additional efforts are focused on the development of translational assays to monitor p97 target engagement and antitumor efficacy in upcoming clinical trials of CB-5083. Conclusion: These data demonstrate that CB-5083 is a potent inhibitor of p97 that translates to tumor growth inhibition in multiple rodent models of human cancer. Furthermore, CB-5083 appears to exhibit greater potency over current proteasome inhibitors that further validate targeting p97 and Protein Homeostasis in the treatment of cancer. Citation Format: Ronan Le Moigne, Steve Wong, Ferdie Soriano, Eduardo Valle, Daniel J. Anderson, Stevan Djakovic, Mary-Kamala Menon, Bing Yao, Julie Rice, Jinhai Wang, Szerenke Kiss Von Soly, Brajesh Kumar, Marta Chesi, P. Leif Bergsagel, Han-Jie Zhou, David Wustrow, Mark Rolfe, F. Michael Yakes. CB-5083 is a novel first in class p97 inhibitor that disrupts cellular Protein Homeostasis and demonstrates anti-tumor activity in solid and hematological models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 951. doi:10.1158/1538-7445.AM2014-951
