Stephan Hacker

Thanks @stephanhacker2.bsky.social ! Very happy to see our photocaged dinucleoside tetraphosphates published. Congrats to the entire team!

Excited that Christina Woo (@thewoolab.bsky.social, @harvard.edu) will visit us for a @led3hub.bsky.social Lecture.

Looking forward to hearing more about her group's exciting research in the fields of #ChemBio, #ChemicalProteomics, #ChemSky and #ProteinDegradation.

www.nature.com/articles/s41...

Very much looking forward to the talk by @kellychibale.bsky.social at the 5th Virtual @chembiotalks.bsky.social and to learn more about the repurposing of #anticancer #kinase inhibitors to treat #malaria.

#ChemBio #ChemSky #DrugDiscovery

Excited that our group was awarded a KIEM grant in collaboration with the @smitslab.bsky.social. Using this grant, we will establish establish new interdisciplinary connections and explore the development of #covalent #antibiotics against C. difficile.

www.staff.universite...

Direct Cellular Screening of Pd-Mediated Arylation of Cyclic Peptide Binders Targeting Ubiquitin Chains: Toward Modulating NEMO Liquid–Liquid Phase Separation Ubiquitination is a critical post-translational modification that regulates key cellular processes such as protein degradation and DNA damage repair. Targeting a specific type of ubiquitin chain (e.g., Lys48 or Lys63-linked ubiquitin chain) via cyclic peptides presents a new strategy to modulate biological processes with therapeutic potential for various diseases. However, such a strategy remains challenging due to the obstacles of cell permeability and bioactivity. Here, we present a new method that directly assesses these parameters by integrating palladium-mediated Cys arylation with direct cellular screening. Using CP4, a previously identified cyclic peptide modulator of Lys63-linked ubiquitin chains, we generated a focused library of arylated analogues and optimized the Pd-mediated arylation for direct cellular screening. We discovered a new analog, CP-P12-ArH, that demonstrated enhanced binding affinity and robust bioactivity, as evidenced by increased γ-H2AX phosphorylation and apoptosis induction in cancer cells. Furthermore, CP-P12-ArH effectively inhibited the in vitro formation of NF-κB essential modulator (NEMO) biomolecular condensates by disrupting the elongation of Lys63-linked ubiquitin chains, offering a novel way to modulate NF-κB signaling. This work establishes a generalizable platform for the rapid optimization of cyclic peptide therapeutics targeting protein–protein interactions.

Interesting paper by the group of Ashraf Brik in @jacs.acspublications.org. Pd-mediated modification of cyclic peptides allows to combinatorially generate S-arylated derivatives and directly screen them for activity in cells.

pubs.acs.org/doi/10....
#ChemSky #ChemBio #DirectToBiology #D2B

Do you know a PhD in #biochemistry or a related field, who deserves an award for their #PhD thesis or publication completed in 2025?

Share with them the #YoungScientistAward of @gdchbiochem.bsky.social. Nominations and applications are possible until October 31st.

#ChemSky #ChemBio @gdch.de

Modulating the Binding Kinetics of Bruton’s Tyrosine Kinase Inhibitors through Transition-State Effects Optimization exercises strive toward increasing the efficacy and selectivity of small molecules toward the target of interest while simultaneously phasing out design elements that lead to off-target interactions. Given the nonequilibrium nature of biological systems, greater reliance should be placed on engineering kinetic selectivity in addition to equilibrium thermodynamic selectivity; however, the rational design of kinetic selectivity is a challenging endeavor. This study presents a systematic knowledge-based approach to the design of inhibitors that vary in their binding kinetics for Bruton’s tyrosine kinase (BTK), a target for treating B-cell malignancies and autoimmune diseases. A detailed kinetic assessment was performed on existing BTK inhibitors, which, together with structural studies, provided critical insights into BTK-inhibitor interactions that control the kinetics of enzyme inhibition. Subsequently, a series of pyrazolopyrimidines was designed with the objective of modifying interactions between the inhibitor and the regulatory (R) spine in the kinase back pocket, which were hypothesized to modulate the stability of the transition state on the binding reaction coordinate. This resulted in the development of BTK inhibitors with extended residence time in which the variation in kon and koff was uncoupled from equilibrium thermodynamic affinity.

Interesting paper by the group of Peter Tonge in @jacs.acspublications.org. They studied the #kinetics of non-covalent #BTK inhibitors. Clinical compounds showed increased residence times, while association rates were nearly constant. pubs.acs.org/doi/10....
#Kinases #DrugDiscovery #ChemSky #ChemBio

Exciting opportunity to join the group of Sylvestre Bonnet in the @led3hub.bsky.social for a #PhD!

If you are an Assistant Professor at Leiden University and interested in this initiative, please reach out to us! (2/2)

Happy that we were awarded a KIEM grant to "Establish a Network to Foster Interdisciplinary Encounters between Assistant Professors" at Leiden University in collaboration with @apnet.bsky.social.
Thank you so much to my co-applicants Lisa Koorneef and Sara Petrollino. (1/2)
www.staff.universite...

Photocaged Dinucleoside Tetraphosphates for Light‐Mediated Activation of 5′ Cap Interactions and Translation In Vitro Photocaged dinucleoside tetraphosphates can be incorporated into mRNA by T7 RNA polymerase. Subsequent irradiation with light activates 5′ cap interactions and translation. These 5′ cap analogs are u...

Interesting paper by the group of @rentmeisterlab.bsky.social in @chemistryeurope.bsky.social. They describe photocaged guanosine-based dinucleotide tetraphosphates like m7Gp4G and their characteristics as RNA cap analogs. chemistry-europe.onl...

A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors Mutant RAS proteins are among the most prevalent drivers of human cancer, and the glycine to aspartic acid mutation at codon 12 (G12D) is the most common variant. Mutation-selective covalent inhibitors spare RAS in healthy tissue and enable extended ...

Always wanted to learn more about targeting carboxylic acids with covalent inhibitors?

Revolution Medicines has now published their work on Zoldonrasib, a clinical stage KRAS G12D inhibitor, in @science.org. Great mechanism by co-engagement of cyclophilin A.

www.science.org/doi/...

Congratulations to our @led3hub.bsky.social colleague @armstrongchembio.bsky.social on receiving funding via an NWO M1 grant. Looking forward to seeing this exciting research into, how the microbiome interacts with and degrades human mucus. www.nwo.nl/en/news/twen...

@leidenscience.bsky.social

Great news that the group of @armstrongchembio.bsky.social was awarded an #NWO M1 grant, to develop new #ChemBio tools to study the interactions between the #microbiome and the human mucus with implications in inflammatory bowel disease and colorectal cancer. www.nwo.nl/en/news/twen...

Ready to be the architect of our community?

APNet is seeking a Community Lead to build a stronger, more connected network for Assistant Professors. This is your chance to shape our culture and make a lasting impact.

Join us! DM or email info@ap-net.nl for details.

If you are interested in peptide-based protein binders, check out this new @biorxivpreprint.bsky.social by the group of @sebastianpomplun.bsky.social of our @led3hub.bsky.social on their computer-based design.

Generative Design of High-Affinity Peptides Using BindCraft Discovering high-affinity ligands directly from protein structures remains a key challenge in drug discovery. We applied BindCraft, a structure-guided generative modeling platform, to de novo design o...

"Generative Design of High-Affinity Peptides Using BindCraft".

New @biorxivpreprint.bsky.social by the group of @sebastianpomplun.bsky.social of our @led3hub.bsky.social!

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

Cc: @leidenscience.bsky.social, @unileiden.bsky.social

Generative Design of High-Affinity Peptides Using BindCraft

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

This is also how I learned about the timSHIFT technology for enrichment-free cysteine profiling first. It can be rewatched here: www.youtube.com/watch?v=nama... (from 1:20:20)

Excited to see this out, he presented this at the ASMS Bruker UGM and I was so impressed!

We look forward to the LED3 Lecture by Anne Osbourn on January 29th, 2026. Her group performs exciting research on plant natural products and their production for drug and chemical discovery programs.

Already mark your calendars! www.universiteitleid...

Gas Phase Separation of Modified Peptides for Activity-Based Protein Profiling Profiling the reactivity of the proteome with amino-acid level resolution requires the identification and quantification of reacted peptides in the presence of abundant unmodified peptides. Affinity-b...

An inspiring paper by the group of Jacob Geri in Analytical Chemistry. They present a method for residue-specific #chemoproteomics without the need for an enrichment step. To achieve this, they developed reagents that shift the ion mobility for gas phase separation. pubs.acs.org/doi/full/10....

The fourth talk of the 5th Virtual ChemBioTalks will be given by @cathleenzeymer.bsky.social. She will talk about her group’s exciting research under the title “Design and directed evolution of artificial photoenzymes”.

Make sure to register for free: https://cvent.me/G1geWW

We are excited to organize an in-person event with a workshop on strategic career development!

This event happens on October 28th in Utrecht. Registration is free for APNet members and 30 € for external attendees.

#Leadership #CareerDevelopment #AssistantProfessor

docs.google.com/form...

New ambassador to the ERC @justynaolko.bsky.social shared her valuable experience during a recent webinar giving information on ERC funding opportunities for researchers in 🇵🇱Poland.

Watch the recording here 👉 bit.ly/ERC2025PL

#Amb4ERC

If you are interested in the activities of @apnet.bsky.social, check out our newest newsletter and consider joining us for our strategic career planning workshop on October 28th.

Curious what APnet is doing for #AssistantProfessors in the #Netherlands?

Check out our newsletter, in which we update you on our activities in the last year and invite you to our in-person workshop "The Academic Edge: A practical workshop in strategic career development".

mailchi.mp/53b3fa7e7...

Interesting and important thought on the importance of funding fundamental research.

Translational research is digging for gold. Basic research is learning where and what to dig. The more funding is diverted to translation, the more we deplete the research ecosystem, driving the supplies of "gold" - immediately translatable findings and innovations - to unsustainably low levels.

Veni grants for 18 Leiden researchers Eighteen researchers from Leiden University have been awarded a Veni grant by the Dutch Research Council (NWO). This grant gives promising young researchers the opportunity to develop their ideas for ...

Excited to learn that @janavolaric.bsky.social received an NWO Veni grant to perform postdoctoral research in our @led3hub.bsky.social.

She will be performing exciting research on the topic of controlling the endocannabinoid system with light.

www.universiteitleiden.nl/en/news/2025...