β-TrCP1, β-TrCP2 and RSK1 or RSK2 inhibitors and methods for sensitizing target cells to apoptosis
Patent Number: US8093043
Executive Summary:
General Description:
Bim (Bcl-2 Interacting Mediator of cell death) is a powerful, proapoptotic member of the Bcl-2 protein family. Alternative mRNA splicing generates three major isoforms: short (BimS), long (BimL), and extra long (BimEL), with BimEL the predominant isoform in most tissues. Upon exposure to stress, such as growth factor deprivation, Bim activates proapoptotic Bak and Bax that, in turn, permeabilize the mitochondrial membrane, causing the release of cytochrome C and the consequent activation of caspases to cause programmed cell death. Several studies suggest that Bim functions as a tumor suppressor. In human cancers, Bim is eliminated via various mechanisms to provide a growth advantage to the tumor cells. However, despite the importance of BimEL in determining cell fate and the fact that its degradation enables tumor cells to escape chemotherapy-induced apoptosis, the cellular machinery responsible for BimEL degradation has not yet been identified. Recently, investigators at NYU have identified the ubiquitin ligase and kinases that target BimEL for proteasomal degradation, and their pharmacological inhibitors, elucidating a critical control mechanism for the apoptotic response.
(RSK inhibitor was BI-D1870 and they silenced βTrCP1/2 using siRNA)
Strengths:
Weaknesses:
Patent Status:
Inventor Bio: Michele Pagano
https://med.nyu.edu/faculty/michele-pagano
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: Issued (Grant date: 2012-01-10)
- Patent Link: https://patents.google.com/patent/US8093043/
- Research Institute: New York University
- Disease Focus: Cancer
- Basis of Invention: The present invention provides a method of sensitizing a cell to cell death or apoptosis comprising contacting a target cell with an effective amount of an inhibitor of β-TrCP1, β-TrCP2, RSK1, or RSK2
- How it works: The inhibitor results in an increase in the amount of BimEL (Bcl-2-Interacting Mediator of cell death, Extra Long isoform) protein compared to the amount of BimEL protein prior to use of an effective amount of the inhibitor
- Lead Challenge Inventor: Michele Pagano
- Inventors: Pagano; Michele (New York, NY), Dehan; Elinor (New York, NY)
- Development Stage: in vitro
- Novelty: Targeting β-TrCP1, β-TrCP2, RSK1, or RSK2 makes it novel
- Clinical Applications: Treatment of cancer by inducing apoptosis in cancer cells
General Description:
Bim (Bcl-2 Interacting Mediator of cell death) is a powerful, proapoptotic member of the Bcl-2 protein family. Alternative mRNA splicing generates three major isoforms: short (BimS), long (BimL), and extra long (BimEL), with BimEL the predominant isoform in most tissues. Upon exposure to stress, such as growth factor deprivation, Bim activates proapoptotic Bak and Bax that, in turn, permeabilize the mitochondrial membrane, causing the release of cytochrome C and the consequent activation of caspases to cause programmed cell death. Several studies suggest that Bim functions as a tumor suppressor. In human cancers, Bim is eliminated via various mechanisms to provide a growth advantage to the tumor cells. However, despite the importance of BimEL in determining cell fate and the fact that its degradation enables tumor cells to escape chemotherapy-induced apoptosis, the cellular machinery responsible for BimEL degradation has not yet been identified. Recently, investigators at NYU have identified the ubiquitin ligase and kinases that target BimEL for proteasomal degradation, and their pharmacological inhibitors, elucidating a critical control mechanism for the apoptotic response.
(RSK inhibitor was BI-D1870 and they silenced βTrCP1/2 using siRNA)
Strengths:
- The new targets may make it a better drug
Weaknesses:
- Has not been tested in animal models yet
Patent Status:
- Priority date: 2008-06-04
- Filing date: 2009-06-04
- Publication date: 2012-01-10
- Grant date: 2012-01-10
Inventor Bio: Michele Pagano
https://med.nyu.edu/faculty/michele-pagano
