Happy to share the final version of this work is now out in @natchembio.nature.com. Lots of additional exciting data! Congrats to all the authors!

Posttranslational modifications remodel proteome-wide ligandability - Nature Chemical Biology

A chemoproteomic strategy reveals how posttranslational modifications reshape protein ligandability across the human proteome, uncovering more than 400 state-dependent interactions, including phosphor...

nature.com

Chris Parker@chrisgparker.bsky.social · last yr.

Excited to share a new preprint from the lab. We show that PTMs like phosphorylation & glycosylation dynamically reshape proteome-wide ligandability in cells, including proteins like KRAS. Great collaboration with the Huang Lab, @forlilab.bsky.social and BMS. www.biorxiv.org/content/10.1...

A @natchembio.nature.com study led by Assoc. Prof. @michael-erb.bsky.social describes a strategy to deliberately discover “molecular glue” degraders by converting existing protein binders into compounds that recruit the cell’s disposal machinery, selectively degrading ENL and BRD4.

New way to intentionally discover molecular glues could expand drug discovery

Scripps Research scientists and colleagues show how drugs that eliminate certain disease-driving proteins can be discovered systematically rather than by chance.

ow.ly

What a thrill to see this out! Our prospective, scalable, and target-centric solution for molecular glue discovery. More thoughts and details here: www.linkedin.com/posts/activi... Paper here: www.nature.com/articles/s41...

High-throughput ligand diversification to discover chemical inducers of proximity - Nature Chemical Biology

Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into mol...

nature.com

Dear friends and colleagues, I am excited to share a preprint describing my take on extracellular targeted protein degradation (eTPD) - a proximity modality termed Sheddase-Targeting Chimeras (SHEDTACs). www.biorxiv.org/content/10.6... 👀

Happy to share the final version of this work out in ACS CS. Inspired by ‘binding-focused’ chemoproteomic methods, we developed a ‘function-focused’ strategy to agnostically identify degradable proteins. This was a big team effort led by @inesforrest.bsky.social and in collaboration with AbbVie.

Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules

Targeted protein degradation (TPD) is an emergent therapeutic strategy with the potential to circumvent challenges associated with targets unamenable to conventional pharmacological inhibition. Among ...

pubs.acs.org

www.biorxiv.org/content/10.1...

Rewiring DNA repair with PARP-based chemical inducers of proximity

Chemical inducers of proximity (CIPs) can elicit durable, and often neomorphic, biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This ...

biorxiv.org

New work out today introducing PCIPs, heterobifunctional chemical inducers of proximity that inhibit DNA repair by recruiting BET proteins to PARP2. Great work uncovering a new form of event-driven pharmacology by Bryce/Eric/Erin and the rest of the team. (1/3) www.biorxiv.org/content/10.1...

Rewiring DNA repair with PARP-based chemical inducers of proximity

Chemical inducers of proximity (CIPs) can elicit durable, and often neomorphic, biological effects through the formation of a ternary complex, even at low equilibrium occupancy of their targets. This ...

biorxiv.org

At the Bioorganic GRC. Ahmed Bedram just gave a very cool talk on genetic code expansion with quadruplet codons. Check out some of the work here www.nature.com/articles/s41...

Efficient genetic code expansion without host genome modifications - Nature Biotechnology

Noncanonical amino acids are efficiently incorporated into proteins by optimizing mRNA codon usage.

nature.com

On my way to #aacr25. I’ll be chairing Part 3 of “Chemistry to the Clinic” tomorrow (4/26 at 2:30) with talks from @dannomura.bsky.social and @xiaoyuzhang.bsky.social. Weather report calls for lots of chemoproteomics, molecular glues, and tough targets. Please join us!

Great news: NIH postbac program is recruiting again! If your grad school plans were affected by program cutbacks or admissions freezes this year I highly encourage you to apply, this could be a perfect opportunity. Please repost. www.training.nih.gov/research-tra...

Delighted to see our paper finally out in @cp-neuron.bsky.social! Together with Ian MacRae, we developed a new toolbox to study microRNAs and used it to find new mechanisms of Purkinje cell development. Please see the tweetorial from researcher extraordinaire @norjin.bsky.social for details.

Nori Zolboot@norjin.bsky.social · last yr.

✨So happy to see part of my PhD work with @lippilab.bsky.social out today in @cp-neuron.bsky.social! ✨ We developed new tools to study microRNA-target networks with greater spatial and temporal resolution and found neuronal subtype- and developmental stage-specific roles:

Congratulations to Prof. Brian Liau, recipient of this year's Eli Lilly Award in Biological Chemistry, and to the excellent presenters who made up this morning's award symposium! @michael-erb.bsky.social, Jesus Gutierrez, @brianliau.bsky.social, Yuh Min Chook, @xiaoyuzhang.bsky.social #ACSSpring2025

excited to celebrate Brian's Eli Lilly award tomorrow and to talk all things molecular glues!

Brian Liau@brianliau.bsky.social · last yr.

Interested in small molecule mechanism? If you’re at #ACSSpring2025, stop by the Eli Lilly Symposium Wed 9am–12pm @ Room 31A in the convention center. Cool talks from @michael-erb.bsky.social, Yuh Min Chook & @xiaoyuzhang.bsky.social. I’ll discuss our program on chemical genomics. Come check it out!

Happy to share a new preprint from our group in collaboration with AbbVie led by graduate student @inesforrest.bsky.social www.biorxiv.org/content/10.1...

Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules

Targeted protein degradation (TPD) is an emergent therapeutic strategy with the potential to circumvent challenges associated with targets unamenable to conventional pharmacological inhibition. Among ...

biorxiv.org

At his last celebration, he said something that stayed with me: "When you start, you think science is about the papers...then you realize it's about the people."

Something that qualifies as big news from my side: I am very happy and excited to announce that I have been appointed as Life Science Director at AITHYRA, a new Research Institute for Biomedical Artificial Intelligence. Find out more in the link and 🧵 below lnkd.in/d_HaGuSE

Make Thalidomide-for-morning-sickness Great Again

Pearl Freier@pearlf.bsky.social · last yr.

Also included in the "Results Act" from Cruz and Roy—congress would be able to override the FDA's decision on a drug: "Grants Congress the authority to disapprove a denied application & override an FDA decision with a majority vote via a joint resolution." #medsky #biosky

🚨 Chemical Biology & Probes study section (formerly SBCB, one of two NIH panels that reviews chemistry #chemsky 🧪) was abruptly POSTPONED w/no specific plans for rescheduling, less than 24h before start. If this affects you call your reps & senators, talk to local news, make your voice heard 📢 👩‍🔬

Congrats Brian and team. Such an elegant discovery. Small molecules can do it all!

Brian Liau@brianliau.bsky.social · last yr.

Today in @nature.com we share our back-to-back stories with Ning Zheng’s lab revealing chemical-genetic convergence between a molecular glue degrader & E3 ligase cancer mutations. 1/5

check out this beautiful science from Xiaoyu, it'll cure your NIH blues for a few minutes

Dan Nomura@dannomura.bsky.social · last yr.

Exciting paper from Xiaoyu Zhang's lab at Northwestern: pubs.acs.org/doi/full/10....

While on clinical service recently, I saw many children who were severely ill due to cancer, flu, and other causes. Sadly this move will mean that healthcare access for many children will be lost, as our institutions suffer from the loss of this critical support: grants.nih.gov/grants/guide...

Not more dramatic than MJ

Science Magazine@science.org · 2y ago

Slow-motion videos reveal tree frogs making some of the most dramatic landings in nature. Learn more: scim.ag/4gTAurn

Thanks for chairing a great session Katherine, really enjoyed it!

Katherine A Donovan@katherinedonovan.bsky.social · 2y ago

I really enjoyed chairing the #AACRCICR session today focused on bivalent degraders. Thank you to Michael Erb, Mikko Taipale, and Xin Zhou for the beautiful talks! #AACRchem24

Maybe a good time to plug this awesome book edited by former PhD students Howard Hang (Scripps), Matt Pratt (USC), Jenn Prescher (UC Irvine), featuring chapters by leaders in the field including @jeremybaskin.bsky.social and a forward by yours truly.

ChemKritzer@chemkritzer.bsky.social · 2y ago

Hey #ChemSky! I teach a primary-literature-based #ChemicalBiology course, and I'd like suggestions for updating the readings. Target audience is 1st-year PhDs and senior undergrads on their way to PhD. Each week I'll add another unit to the thread for your suggestions. Thanks for your help!!

They disrupt nuclear aggregate formation in patient cells, correct relevant splicing defects, and fully reverse myotonia in mice. And they do all this while preserving the things we know and love about small molecules, including broad biodistribution and oral bioavailability.

Saturation mutagenesis CRISPR screen to map CREs of PD-L1 + TFs CRISPR LoF screen to identify known & novel trans-regulators + CUT&RUN to confirm new regulators + HiChIP enhancers/promoters contact maps Very impressive work by @nevillesanjana.bsky.social www.biorxiv.org/content/10.1...

Paired CRISPR screens to map gene regulation in cis and trans

Recent massively-parallel approaches to decipher gene regulatory circuits have focused on the discovery of either cis -regulatory elements (CREs) or trans -acting factors. Here, we develop a scalable ...

biorxiv.org

Cool paper from Fleur Ferguson’s lab: onlinelibrary.wiley.com/doi/abs/10.1...

A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharm...

onlinelibrary.wiley.com

Dual-ligase PROTACs: a novel approach for enhancing TPD. By recruiting two distinct E3 ligases within a single molecule, we amplify degradation efficacy & potentially mitigate resistance occurrence. Great collabo with the Ciulli lab & friends at Promega. pubs.acs.org/doi/10.1021/...

Leveraging Dual-Ligase Recruitment to Enhance Protein Degradation via a Heterotrivalent Proteolysis Targeting Chimera

Proteolysis targeting chimera (PROTAC) degraders are typically bifunctional with one E3 ligase ligand connected to one target protein ligand via a linker. While augmented valency has been shown with trivalent PROTACs targeting two binding sites within a given target protein, or used to recruit two different targets, the possibility of recruiting two different E3 ligases within the same compound has not been demonstrated. Here we present dual-ligase recruitment as a strategy to enhance targeted protein degradation. We designed heterotrivalent PROTACs composed of CRBN, VHL and BET targeting ligands, separately tethered via a branched trifunctional linker. Structure–activity relationships of 12 analogues qualifies AB3067 as the most potent and fastest degrader of BET proteins, with minimal E3 ligase cross-degradation. Comparative kinetic analyses in wild-type and ligase single and double knockout cell lines revealed that protein ubiquitination and degradation induced by AB3067 was contributed to by both CRBN and VHL in an additive fashion. We further expand the scope of the dual-ligase approach by developing a heterotrivalent CRBN/VHL-based BromoTag degrader and a tetravalent PROTAC comprising of two BET ligand moieties. In summary, we provide proof-of-concept for dual-E3 ligase recruitment as a strategy to boost degradation fitness by recruiting two E3 ligases with a single degrader molecule. This approach could potentially delay the outset of resistance mechanisms involving loss of E3 ligase functionality.

pubs.acs.org

Excited to share our work investigating how ligand residence time influences targeted protein degradation outcomes at scale, and how we can combine kinetic scout degrader approaches with mathematical modeling to accelerate hit finding and optimization! onlinelibrary.wiley.com/doi/abs/10.1...

A Kinetic Scout Approach Accelerates Targeted Protein Degrader Development

Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharm....

onlinelibrary.wiley.com