6 research outputs found
Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation
Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets
Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation
Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets
Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation
Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets
Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation
Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets
Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation
Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets
Exploiting the Cullin E3 Ligase Adaptor Protein SKP1 for Targeted Protein Degradation
Targeted
protein degradation with proteolysis targeting chimeras
(PROTACs) is a powerful therapeutic modality for eliminating disease-causing
proteins through targeted ubiquitination and proteasome-mediated degradation.
Most PROTACs have exploited substrate receptors of Cullin-RING E3
ubiquitin ligases such as cereblon and VHL. Whether core, shared,
and essential components of the Cullin-RING E3 ubiquitin ligase complex
can be used for PROTAC applications remains less explored. Here, we
discovered a cysteine-reactive covalent recruiter EN884 against the
SKP1 adapter protein of the SKP1-CUL1-F-box containing the SCF complex.
We further showed that this recruiter can be used in PROTAC applications
to degrade neo-substrate proteins such as BRD4 and the androgen receptor
in a SKP1- and proteasome-dependent manner. Our studies demonstrate
that core and essential adapter proteins within the Cullin-RING E3
ubiquitin ligase complex can be exploited for targeted protein degradation
applications and that covalent chemoproteomic strategies can enable
recruiter discovery against these targets