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womenintpd.bsky.social
Women in TPD & Induced Proximity
@womenintpd.bsky.social
670 followers 490 following 73 posts
Celebrating the achievements and discoveries made by the brilliant women in targeted protein degradation and induced proximity!
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · 2d
If you are in the Boston area at the end of October do not miss our free, in-person networking event on Wednesday, October 29th from 5:30-7:30pm! Thank you so much to Kymera Therapeutics for hosting. Register below at this link:
www.eventbrite.com/e/women-in-t...
Women in TPD - In Person Networking Event (hosted by Kymera Therapeutics
In conjunction with the 8th TPD & Induced Proximity Summit
www.eventbrite.com
womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Jun 16
Don't have a binder to your favorite E3 yet - no problem! Congratulations to lead author Yunan Zheng and colleagues at AbbVie on their work using non-canonical amino acids in E3s which can be linked via click chemistry to a target binder.
pubs.acs.org/doi/10.1021/...
In-Cell Approach to Evaluate E3 Ligases for Use in Targeted Protein Degradation
A major challenge in evaluating the suitability of ∼700 known and putative E3 ligases for target protein degradation (TPD) is the lack of ligase-specific binders. Here, we use genetic code expansion (...
pubs.acs.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Jun 16
New preprint out led by Patricia Blanco-Gabella and colleagues at University of Barcelona looking at how hydrogen bond interactions can stabilize ternary complexes and be better predicted computationally to enable more rational design.
chemrxiv.org/engage/chemr...
Understanding the role of H-bonds in the stability of molecular glue-induced ternary complexes
Protein-protein interaction (PPI) networks play a central role in many biological processes and thus the possibility of modulating them using small molecules offers several biomedical and biotechnolog...
chemrxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · May 16
A look at the next generation PROTACs from the laboratory of Anne Sophie Voisen-Chiret at University of Caen Normandy!
www.sciencedirect.com/science/arti...
PROTAC 2.0: Expanding the frontiers of targeted protein degradation
Proteolysis targeting chimera (PROTAC) technology has revolutionized targeted protein degradation via the ubiquitin–proteasome system. Despite their e…
www.sciencedirect.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · May 16
New thought piece and review co-led by Clara Inghelram from FMI, Basel on how shifting affinity of weak interactions with E3 ligases with molecular glues can ultimately lead to robust degradation. Nice thermodynamic model at the end.
www.sciencedirect.com/science/arti...
Primed for degradation: How weak protein interactions enable molecular glue degraders
Molecular glues are small drug-like molecules that induce de novo protein–protein interactions or facilitate pre-existing weak interactions between pr…
www.sciencedirect.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · May 5
Expanded covalent DCAF16 binders that allow for improved degradation of neosubstrates and engage two different cysteines. Congratulations to lead author Lauren Orr and colleagues at UC Berkeley!
www.biorxiv.org/content/10.1...
DCAF16-Based Covalent Degradative Handles for the Modular Design of Degraders
Targeted protein degradation (TPD) is a powerful strategy for targeting and eliminating disease-causing proteins. While heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) are more modular, th...
www.biorxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · May 5
Congratulations to co-author Valentina Spiteri and colleagues at CeTPD Dundee and CeMM on this comprehensive review on degraders, their use in oncology, and future disease indication opportunities.
www.nature.com/articles/s41...
Targeted protein degradation for cancer therapy - Nature Reviews Cancer
Targeted protein degradation (TPD) is an emerging pharmacological modality in cancer therapy. In this Review, Hinterndorfer et al. outline the mechanistic bases of TPD and discuss the characteristics,...
www.nature.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · May 5
New review from authors Annabel Cardno, Bryony Kennedy, and Catherine Lindon from University of Cambridge comes a review of the important aspects to consider for obtaining optimal degrader activity. From localization to activity of ligase to target accessibility!
www.nature.com/articles/s42...
Cellular parameters shaping pathways of targeted protein degradation - Communications Biology
This review discusses the cellular pathways mediating Targeted Protein Degradation approaches and points to some gaps in our understanding of the biology of novel therapeutic tools such as PROTACs.
www.nature.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · May 5
New preprint out from the lab of Cheryl Arrowsmith and colleagues at University of Toronto and the SGC comes ProtacID, a BioID approach to understand both the productive and non-productive interactors of degraders.
www.biorxiv.org/content/10.1...
Characterization of PROTAC specificity and endogenous protein interactomes using ProtacID
Here we describe ProtacID, a flexible BioID (proximity-dependent biotinylation)-based approach to identify PROTAC-proximal proteins in living cells. ProtacID analysis of VHL- and CRBN-recruiting PROTA...
www.biorxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 16
Work out led by Alessandra Salerno and colleagues at CeTPD Dundee introducing ferrocene into PROTAC linkers ("FerroTACs") to give them rotational flexibility. Congratulations!
pubs.acs.org/doi/10.1021/...
Rational Design of PROTAC Linkers Featuring Ferrocene as a Molecular Hinge to Enable Dynamic Conformational Changes
Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and degradation of a target protein via recruitment to an E3 ligase. The linker influences many steps of ...
pubs.acs.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 16
Degraders meet agriculture! Congratulations to Gina Morgan and colleagues at Oerth Bio on their work applying targeted protein degradation to the fall armyworm.
www.nature.com/articles/s42...
Pioneering protein degradation for agricultural applications - Communications Biology
Development of VHL-recruiting PROTACs that degrade fall armyworm sfBRD3 and sfWDS proteins with high potencies in Sf9 cells and in full larvae, establishing the PROTAC modality as promising for agricu...
www.nature.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 16
Don’t miss these two talks tomorrow by Charlotte Crowe and Alessandra Salerno!
Great series by DFCI with free registration:
www.danafarbertargetedproteindegradation.org
womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 3
Induced proximity modalities at the cell surface! Comprehensive review of emerging approaches and therapeutic possibilities by Carolyn Bertozzi and colleagues at Stanford!
www.nature.com/articles/s41...
Induced proximity at the cell surface - Nature Biotechnology
Technologies to modulate induced proximity at the cell surface advance the manipulation of diverse biological responses.
www.nature.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 3
New preprint out co-led by Hannah Lloyd and Christina Woo at Harvard along with colleagues at the Broad and CeTPD Dundee gives insight on how to detect and discover native substrates of CRBN!
www.biorxiv.org/content/10.1...
A method for the detection and enrichment of endogenous cereblon substrates
C-Terminal cyclic imides are posttranslational modifications on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modificati...
www.biorxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 3
From the team of Angela Koehler and colleagues at MIT, an excellent analysis of how CDK9 degradation differs from CDK9 inhibition with respect to Myc regulation. Congratulations!
www.cell.com/cell-chemica...
Targeted degradation of CDK9 potently disrupts the MYC-regulated network
Toure et al. investigate a known challenge in CDK9 inhibition—the compensatory increase in MYC levels. They demonstrate that a selective CDK9 degrader with rapid kinetics circumvents this effect, prov...
www.cell.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 2
What type of ubiquitylation and branching do you need to drive degradation? See the answer below in this new paper from Brenda Schulman and her team!
www.cell.com/molecular-ce...
UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains
Ubiquitin chains determine the fates of their modified proteins, including proteasomal degradation. Kiss et al. present UbiREAD, a technology to monitor cellular degradation and deubiquitination at hi...
www.cell.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 2
Excellent overview from Wenqing Xu and Christina Woo on all their learnings about Cereblon, its native activity, and considerations for its use in targeted protein degradation!
pubs.acs.org/doi/full/10....
Probing the E3 Ligase Adapter Cereblon with Chemical Biology
ConspectusThe E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological d...
pubs.acs.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Apr 2
Work out co-led by Meredith Nix and colleagues at Stanford using induced proximity to regulate transcription! Here they link up some of my favorite chromatin regulators, CBP and EP300, to BCL6 with their TCIP3 and show this can activate pro-apoptotic genes.
www.biorxiv.org/content/10.1...
A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death
Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provi...
www.biorxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 22
Preprint out of induced proximity between EWS/FLI1 with BCL6 leads to cell death by a new TCIP called EB-TCIP. Work out from teams at Stanford and DFCI and co-led by the lab of Kimberly Stegmaier!
www.biorxiv.org/content/10.1...
Rewiring the fusion oncoprotein EWS/FLI1 in Ewing sarcoma with bivalent small molecules
Deregulated transcription is a defining hallmark of cancer, especially pediatric malignancies, which are frequently driven by fusion transcription factors. Targeting transcription factors directly has...
www.biorxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 22
BLUEs - molecular glues of the BRCC36 complex (BRISC) which stabilize it in an autoinhibited dimer, leading to DUB inhibition on its downstream target - Type I interferon receptors. Congratulations to lead author Francesca Chandler and colleagues at University of Leeds
www.nature.com/articles/s41...
Molecular glues that inhibit deubiquitylase activity and inflammatory signaling - Nature Structural & Molecular Biology
The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactiv...
www.nature.com
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 20
Congratulations Breanna Zerfas and teams at DFCI on this linkerless PROTAC degrading and ER-stress transmembrane protein IRE1α with CRBN!
pubs.rsc.org/en/content/a...
Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α
IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or...
pubs.rsc.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 19
Congratulations to Abigail Brewer and Jin-Feng Zhao at University of Dundee for winning the Howard Elder Prize for their work on targeted dephosphorylation! www.ppu.mrc.ac.uk/news/abigail...
Abigail Brewer and Jin-Feng Zhao awarded the Howard Elder Prize 2024 for outstanding cancer research | MRC PPU
Abigail Brewer, a recently graduated PhD student, and Jin-Feng Zhao, a postdoctoral researcher, from Prof. Gopal Sapkota’s lab at the MRC Protein Phosphorylation and Ubiquitylation Unit have been awar...
www.ppu.mrc.ac.uk
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 13
New induced proximity work out co-led by Ella Livnah and colleagues at the Weizmann Institute introducing PINCHs (Polymerization Inducing Chimeras)! These bifunctional molecules cause homomeric proteins to start polymerizing into supramolecular structures.
www.biorxiv.org/content/10.1...
A pharmacological modality to sequester homomeric proteins
Molecules that can perturb protein-protein interactions have an immense impact on chemical biology and therapeutics. However, such compounds typically rely on accessory proteins to function, such as E...
www.biorxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 10
New preprint out co-led Nur Kocaturk along with colleagues at University of Dundee and Bio-Techne showing a direct-to-biology discovery of a brain penetrant degrader of GSK3. Congratulations to all!
chemrxiv.org/engage/chemr...
Discovery of a CNS active GSK3 degrader using orthogonally reactive linker screening
Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative d...
chemrxiv.org
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womenintpd.bsky.social
Women in TPD & Induced Proximity @womenintpd.bsky.social · Mar 10
Work out led by Elisia Villemure, Joyce Liu, and colleagues at Genentech designing a monovalent degrader of SMARCA2/4 starting from a bromodomain binder. Great follow-up work to show it was UPS driven and via recruitment of E3 ligase component FBXO22!
www.biorxiv.org/content/10.1...
Rational design of potent small molecule SMARCA2/A4 (BRM/BRG1) degraders acting via the recruitment of FBXO22
www.biorxiv.org
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