Severin Lechner

Inhibitors supercharge kinase turnover through native proteolytic circuits - Nature Inhibitor-induced kinase degradation is a common event that positions supercharging of endogenous degradation circuits as an alternative to classical proximity-inducing degraders.

Excited to share our work on inhibitors turning degraders now out: doi.org/10.1038/s415...

🧬Kinase inhibitors that degrade?
New study by CeMM, @aithyra.bsky.social & @irbbarcelona.org reveals that kinase inhibitors can also trigger the degradation of their target proteins, becoming a new tool for drug development & #TDP research.
➡️ More: bit.ly/3LY6jor
📄 Paper: bit.ly/43MffU1

New preprint 🚨 We systematically measured 17 million phospho-specific dose-response curves (133 kinase inhibitors × 5 cell lines) to decrypt the kinases that shape the human phosphoproteome. We show that drug perturbation potency (not effect size) links kinases to substrates while controlling FDR.

Chemical proteomics decrypts the kinases that shape the dynamic human phosphoproteome Mass-spectrometry-based phosphoproteomics enables the analysis of thousands of protein phosphorylation events across the human proteome. However, there is a lack of scalable, hypothesis-free, and stat...

Did you ever come across a phosphosite in your proteomics data for which nothing was known? - I bet so!

We have developed a new strategy termed "potency coherence analysis" that leverages the drug potency dimension in decryptM to decode the kinases that shape the human phosphoproteome.

Read more:

Peptide-RNA photo-crosslinks with tunable RNA chain map protein-RNA interfaces Photo-crosslinking mass spectrometry enables the identification of protein-RNA interactions in living cells, pinpointing interaction interfaces at single-amino acid resolution. However, current isolat...

New preprint: We isolate peptide–RNA photo-crosslinks with tunable RNA chains from living cells for mass spec. This maps over 4,700 crosslinking sites across 744 proteins and offers the first glimpse into the RNA sequences in crosslinks by MS. Read here: doi.org/10.1101/2025...

Computational Approaches for Pathway‐Centric Analysis of Protein Post‐Translational Modifications Protein function is dynamically modulated by post-translational modifications (PTMs). Many different types of PTMs can nowadays be identified and quantified at a large scale using mass spectrometry. ...

Our new review paper about Pathway-Centric PTM Data Analysis is out this week in #Proteomics!
We cover databases, enrichment tools, software for pathway reconstruction, and full-fledged platforms that help to interpret high-throughput PTM datasets.
Check it out here: doi.org/10.1002/pmic...

DeCrypt KRAS signaling using all the common inhbiitors! This one had so many steps to get behind the paywall of that I thought I was trying to find a certain global leader's name thousands of ti...

They DecryptED all the KRAS small molecule inhibitors! Including cysteine enrichments! proteomicsnews.blogspot.com/2025/08/decr...

Measuring & modeling nucleic acids is very useful and needed.

Yet, it provides a partial view.

It misses many biological processes, from signal transduction and metabolic fluxes, through enzyme activities to therapeutic effects.

bsky.app/profile/slav...

@aithyra.bsky.social Opening Symposium "AI for Life Science" with Nobel Laureate Frances Arnold as keynote speaker in addition to an outstanding line up of speakers on a variety of topics across biological scales and data modalities.

Registration is now open at cemm.at/aithyra-symp...

The human proteome with direct physical access to DNA Zero-distance photo-crosslinking reveals direct protein-DNA interactions in living cells, enabling quantitative analysis of the DNA-interacting proteome on a timescale of minutes with single-amino-aci...

🚨Our new paper is online🚨
We use zero-distance⚡photo-crosslinking⚡to reveal direct protein-DNA interactions in living cells, enabling quantitative analysis of the DNA-interacting proteome on a timescale of minutes. #DNA #Chromatin #Proteomics
www.cell.com/cell/fulltex...

Key takeaways:
a) every second HDAC inhibitor with a phenylhydroxamic warhead inhibits MBLAC2
b) NME1-4 and HINT1 are now targetable with small molecule inhibitors
c) chemoproteomics is always good for surprises 🙂

We characterized HINT1 and NME1-4 inhibition with enzyme activity assays, molecular docking, and co-crystal structures.

As often seen with chemoproteomic approaches, we made some unexpected but exciting findings: several molecules bound to the yet undrugged proteins NME1-4 and HINT1.

Having profiled over 100 molecules, we derive rules for which HDAC pharmacophores are prone to inhibit MBLAC2. We also found nanomolar MBLAC2 inhibitors with >30-100-fold selectivity over HDACs.

Here, we profiled a hand-picked library of metalloenzyme inhibitors. This uncovered several unreported off-targets of HDAC inhibitors and confirmed MBLAC2 as a frequent off-target, also for purportedly selective inhibitors such as SW-100.

Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target - Nature Chemical Biology Lechner et al. used an affinity-based chemical proteomics approach to investigate the target landscape of HDAC inhibitors, and identified an extracellular vesicle regulator MBLAC2 as a universal off-t...

Using a chemoproteomic competition assay, we previously identified MBLAC2 as off-target of more than 20/50 profiled HDAC inhibitors (www.nature.com/articles/s41...)

Paper alert!
We report the first inhibitors for nucleoside kinases NME1-4 and for the nucleotide-binding protein HINT1.
On top, we provide probes for MBLAC2, an off-target of every second (!) hydroxamic acid-based HDAC inhibitor!
tinyurl.com/yh92vh6b
👇🧵

Unifying the analysis of bottom-up proteomics data with CHIMERYS - Nature Methods CHIMERYS is a spectrum-centric and data acquisition method-agnostic algorithm for the analysis of MS2 spectra. It is capable of deconvoluting any MS2 spectrum, regardless of whether it was acquired by...

One algorithm to rule them all? CHIMERYS bridges the gap — DDA,DIA and PRM — together at last!
With #CHIMERYS, we can now directly compare DDA and DIA data — 🍎 to 🍎 finally made possible.
doi.org/10.1038/s41592-025-02663-w
#KusterLab #WilhelmLab #MSAID #Proteomics

🚨 Hiring Alert – Senior Scientist (Biology) 🚨
My lab is looking for a senior scientist to lead functional genomics efforts and decode how small molecules reshape biology
🧬 Lead screens
🤝 Collaborate with top-tier AI/chemistry/biology minds

Interested? then apply: cemm.onlyfy.jobs/job/t7lhh1kz

Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq Targeted protein degradation (TPD) is an emerging therapeutic modality in which small molecules are used to recruit targets to the natural protein degradation machinery of the cell. Molecular glue deg...

🚨 Rational discovery of VHL molecular glues. New Preprint from @amgen.bsky.social Induced Proximity group led by postdoc Jonathan Bushman reports the discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq. Read on for details. 🧵1/8 www.biorxiv.org/content/10.1...

Less than 3 weeks left⏳Register by April 7 for the #Ubiquitin & Friends Symposium, May 8-9, in beautiful Vienna!
Fantastic guest speakers, open slots for short talks, flash talks& posters: Great opportunity for students & #ECRs! Register soon to save your spot➡️ www.protein-degradation.org/symposium/

Did you recently complete a ChemBio/MedChem PhD (non-UK) and are looking for the next challenge? I am seeking a prospective applicant for a Newton Fellowship with an exciting project in targeted protein dephosphorylation! Please reach out to e.devita@qmul.ac.uk
royalsociety.org/grants/newto...

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