DEVELOPMENT OF A NOVEL FIRST-IN-CLASS ORAL INHIBITOR OF THE NOTCH PATHWAY.
(Abstract release date: 05/19/16)
EHA Library. Lehal R. 06/10/16; 133148; P160
Dr. Rajwinder Lehal
Contributions
Contributions
Abstract
Abstract: P160
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway.
Aims
Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule -secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors.
Methods
Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus.
Results
CB-103 has shown the ability to block NOTCH signalling in human T cell acute lymphoblastic leukemia cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. Furthermore, CB-103 has shown a remarkable activity in exvivo and invivo patient derived models of human T-ALL harbouring activation of the NOTCH pathway. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors.
Conclusion
Based on invivo pharmacokinetic/ADME studies, CB-103 has been nominated as development candidate for further preclinical and clinical development.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Notch signaling, T cell acute lymphoblastic leukemia, Targeted therapy
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway.
Aims
Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule -secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors.
Methods
Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus.
Results
CB-103 has shown the ability to block NOTCH signalling in human T cell acute lymphoblastic leukemia cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. Furthermore, CB-103 has shown a remarkable activity in exvivo and invivo patient derived models of human T-ALL harbouring activation of the NOTCH pathway. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors.
Conclusion
Based on invivo pharmacokinetic/ADME studies, CB-103 has been nominated as development candidate for further preclinical and clinical development.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Notch signaling, T cell acute lymphoblastic leukemia, Targeted therapy
Abstract: P160
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway.
Aims
Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule -secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors.
Methods
Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus.
Results
CB-103 has shown the ability to block NOTCH signalling in human T cell acute lymphoblastic leukemia cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. Furthermore, CB-103 has shown a remarkable activity in exvivo and invivo patient derived models of human T-ALL harbouring activation of the NOTCH pathway. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors.
Conclusion
Based on invivo pharmacokinetic/ADME studies, CB-103 has been nominated as development candidate for further preclinical and clinical development.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Notch signaling, T cell acute lymphoblastic leukemia, Targeted therapy
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway.
Aims
Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule -secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors.
Methods
Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus.
Results
CB-103 has shown the ability to block NOTCH signalling in human T cell acute lymphoblastic leukemia cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. Furthermore, CB-103 has shown a remarkable activity in exvivo and invivo patient derived models of human T-ALL harbouring activation of the NOTCH pathway. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors.
Conclusion
Based on invivo pharmacokinetic/ADME studies, CB-103 has been nominated as development candidate for further preclinical and clinical development.
Session topic: Acute lymphoblastic leukemia - Biology 2
Keyword(s): Notch signaling, T cell acute lymphoblastic leukemia, Targeted therapy
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