Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Kathleen M. Sakamoto,Kyung Bo Kim,Akiko Kumagai,Frank Mercurio,Craig M. Crews,Raymond J. Deshaies +5 more
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TLDR
It is shown that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner, which may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.Abstract:
The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.read more
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Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
TL;DR: A chemical proteomics strategy identifies DCAF16—a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases—as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins.
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Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras.
TL;DR: It is shown here that the hetero-bifunctional molecule can be formed intracellularly by bio-orthogonal click combination of two smaller precursors, and expected this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degradation.
Journal ArticleDOI
Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation
Alexandru D. Buhimschi,Haley A Armstrong,Momar Toure,Saul Jaime-Figueroa,Timothy L. Chen,Amy Lehman,Jennifer A. Woyach,Amy J. Johnson,John C. Byrd,Craig M. Crews +9 more
TL;DR: A PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK, and a lead PROTAC, MT-802, from several candidates on the basis of its potency to induce BTK knockdown.
Journal ArticleDOI
The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications.
TL;DR: Known inhibitors of the proteasome and their molecular mechanisms as well as ongoing developments and promising avenues for targeting substrate-specific E3 ligases that are likely to yield a new class of therapeutics that will serve and complement the armamentarium of anticancer drugs are reviewed.
Journal ArticleDOI
Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands
David Remillard,Dennis L. Buckley,Joshiawa Paulk,Gerard L. Brien,Matthew Sonnett,Matthew Sonnett,Hyuk-Soo Seo,Shiva Dastjerdi,Martin Wühr,Sirano Dhe-Paganon,Scott A. Armstrong,James E. Bradner +11 more
TL;DR: The first BRD9-directed chemical degraders are created, through iterative design and testing of heterobifunctional ligands that bridge theBRD9 bromodomain and the cereblon E3 ubiquitin ligase complex, and reveal the tractability of non-BET bromidomain containing proteins to chemical degradation.
References
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