Stephan HackerJan 4
2025 was a year full of great scientific discoveries and breakthroughs. Here, I want to highlight 10 papers that got me really excited. Of course, this is a highly subjective selection and I am sure I am forgetting some papers that I would love to include, but here it goes: (1/12)
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Chemical Proteomics without an enrichment step: The group of Jacob Geri with first author Peter Bellotti published a method for residue-specific #chemoproteomics without the need for an enrichment step. To achieve this, they developed reagents that shift the ion mobility of modified peptides for gas phase separation. In my eyes, this is a super exciting concept that could really move the field forward in the future. (2/12)
https://pubs.acs.org/doi/full/10.1021/acs.analchem.5c03300
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Cellular profiling of kinases: The group of Mario van der Stelt of our @LED3hub with first authors Joel Ruegger and Berend Gagestein published CellEKT for profiling of the cellular targets of kinase inhibitors. There is a lot of potential in profiling the selectivity of this important drug class, which is further developed in the company Omivera (https://omivera.com/) by Anthe Janssen, Joel Ruegger and Zoe Voggelaar. (3/12)
https://www.sciencedirect.com/science/article/pii/S1535947625000593
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Covalent inhibitors targeting RNA: The groups of Ronald Micura and Alexandra Lusser presented covalent binders to structured RNA based on alkyl halides and alkyl mesylates for the preQ1 and Pepper aptamers that engage their targets in vitro and in cells. Very curious to follow further, how RNA-targeting small molecules expand the druggable space. (4/12)
https://www.nature.com/articles/s41589-024-01801-3
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Natural substrates for Cereblon: Cereblon is one of the most used E3 ligases for degraders. Nevertheless, the biological function of the underlying cyclic imid ligands was long underexplored. After showing that C-terminal cyclic imids on proteins are ligands for cereblon, the group of Christina Woo showed that PCMT1 can install them on asparagines via SAM-dependent methyl ester formation, which then leads to degradation using cereblon. (5/12)
https://www.nature.com/articles/s41589-025-02106-9
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Efficiently screening for protein binders: The group of Sebastian Pomplun of our @LED3hub developed self-encoded libraries (SELs) that allow affinity-selection MS-based screening of protein binders from >500,000 member libraries in a single experiment without the need for a barcode. Very excited to follow further, how these methods enable identification of binders for high-value targets. (6/12)
https://www.nature.com/articles/s41467-025-65282-1
Jan 4 at 6:48amWeb
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A covalent KEAP1 activator in the clinics: A team at Vividion led by Matt Patricelli developed a covalent molecular glue for KEAP1, which leads to suppression of NRF2-dependent cancer growth. Excited to see, how the three clinical programs that Vividion built based on #CovalentInhibitors discovered by #ChemicalProteomics will progress. (7/12)
https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-25-1187/771133/A-covalent-allosteric-molecular-glue-suppresses?searchresult=1
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Covalent Inhibitors targeting lysines: The groups of Jean-Marie Lehn and Oleksandr Koniev developed 6-fluorosalicylaldehydes into tools that form imines with lysines. This activates them for irreversible modification of cysteines via SNAr. There is definitely still a big need for covalently reactive groups that are amenable to #DrugDiscovery and are directed at other amino acids than cysteine. Surely, there is still a lot to be discovered. (8/12)
https://pubs.acs.org/doi/10.1021/jacs.4c15421
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Efficient discovery of Covalent Inhibitors using a Direct-to-Biology Approach. A team of GSK around Jacob Bush showcased the power of single- and multi-step direct-to-biology approaches by efficiently developing a potent, cell-active acrylamide inhibitor for WRN helicase. Very excited about the potential of D2B in covalent drug discovery. (9/12)
https://chemrxiv.org/engage/chemrxiv/article-details/67c5b1e06dde43c9084c1006
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Synthesis of complex chemical structures by atom insertion: The Max Hansmann group published that Ph2SCN2 introduces a single sp3 carbon atom into molecules to form up to 4 C–C σ-bonds in one step without using transition metal catalysis giving exciting, highly 3-dimensional structures. Such development of powerful chemical tools will surely drive a lot of discoveries in #DrugDiscovery and #ChemBio. (10/12)
https://www.science.org/doi/10.1126/science.ads5974
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New antibiotic for Clostridioides difficile infections: The groups of Nathaniel Martin of our @LED3hub and of Wiep Klaas Smits of the LUMC published the powerful semisynthetic guanidino lipoglycopeptide EVG7 to treat Clostridioides difficile infections. While I saved #antibiotic discovery for last, there is surely still a high need for new antibiotics, may they be natural products, semisynthetic derivatives or fully synthetic compounds. (11/12)
https://www.nature.com/articles/s41467-025-64067-w
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Overall, I hope that 2026 will yield at least the same degree of scientific progress as 2025. (12/12)

#Chemistry #ChemBio #Science #Antibiotics #Synthesis #TPD #Degrader #Proteomics #Kinases #RNA #Screening #CovalentInhibitors #DirectToBiology