Interesting ChemRxiv preprint by the group of Katrin Rittinger. They use enantiomeric pairs of covalent inhibitors to profile ligandable cysteines in the proteome. Interesting use of machine learning to predict new compounds that can add most to the ligandable space.
https://doi.org/10.26434/chemrxiv.15002030/v1
#ChemicalProbes #ChemicalProteomics #ProteoProbes #Chemistry #ChemBio #Ligandability #Cysteine #CovalentInhibitor
Part 27, drug discovery on an “Undruggable” Target. K‑Ras is a small intracellular GTPase that functions as a molecular switch, activating mitogenic signaling pathways in response to growth factors. Direct attempts to inhibit this oncogene with competitive drugs at its GTP‑binding site failed because of its picomolar affinity for GTP and the high intracellular GTP concentration. Mutations in the K‑Ras pathway, such as K‑RasG12C, render the protein constitutively active, driving uncontrolled proliferation and e.g. contributing to ~40% of K‑Ras–driven lung cancers. Until 2013, K‑Ras was considered non‑druggable, but this view shifted when the Shokat lab revealed a hidden allosteric regulatory pocket in K‑RasG12C that becomes accessible when small electrophilic molecules covalently bind the mutant cysteine. This covalent engagement displaces key “protein switches,” biases the protein toward GDP over GTP conformation and prevents Raf binding, thereby shutting down MAPK signaling. Following this breakthrough, Amgen optimized the Shokat group’s early acrylamide fragments into an in‑vivo‑suitable tool compound, ARS‑1620. Extensive crystallography and docking guided the medicinal chemistry cycles that ultimately produced the highly decorated drug sotorasib (approved in 2021). In phase 3 trials in K‑RasG12C‑mutant lung cancer, sotorasib improved progression‑free survival compared with docetaxel, although overall survival was unchanged. That outcome is somewhat disappointing, but there is hope that real‑world drug combination strategies may yet deliver meaningful gains in overall survival.
Another interesting #SciComm post by Stan Van Boeckel! K-Ras #DrugDiscovery from being considered #Undruggable to the clinical approval of the #covalent #inhibitor Sotorasib.
#Science #ScienceCommunication #Medicines #StoryTelling #Cancer #KRAS #CovalentInhibitor
Part 27, drug discovery on an “Undruggable” Target. K‑Ras is a small intracellular GTPase that functions as a molecular switch, activating mitogenic signaling pathways in response to growth factors. Direct attempts to inhibit this oncogene with competitive drugs at its GTP‑binding site failed because of its picomolar affinity for GTP and the high intracellular GTP concentration. Mutations in the K‑Ras pathway, such as K‑RasG12C, render the protein constitutively active, driving uncontrolled proliferation and e.g. contributing to ~40% of K‑Ras–driven lung cancers. Until 2013, K‑Ras was considered non‑druggable, but this view shifted when the Shokat lab revealed a hidden allosteric regulatory pocket in K‑RasG12C that becomes accessible when small electrophilic molecules covalently bind the mutant cysteine. This covalent engagement displaces key “protein switches,” biases the protein toward GDP over GTP conformation and prevents Raf binding, thereby shutting down MAPK signaling. Following this breakthrough, Amgen optimized the Shokat group’s early acrylamide fragments into an in‑vivo‑suitable tool compound, ARS‑1620. Extensive crystallography and docking guided the medicinal chemistry cycles that ultimately produced the highly decorated drug sotorasib (approved in 2021). In phase 3 trials in K‑RasG12C‑mutant lung cancer, sotorasib improved progression‑free survival compared with docetaxel, although overall survival was unchanged. That outcome is somewhat disappointing, but there is hope that real‑world drug combination strategies may yet deliver meaningful gains in overall survival.
Great talk by Phillip Yesley from the group of Wim Velema at #Lunteren2026.
He discussed the use of mutational profiling to find covalent ligands for structured #RNA using acyl imidazoles as the reactive group.
https://onlinelibrary.wiley.com/doi/10.1002/ange.202517243
#Chemistry #ChemBio #Covalent #CovalentInhibitor
Very happy that Marnix Roseboom represented our group of the @LED3hub with a very well-attended talk at #NWOCHAINS. He reported on his #PhD work on developing #ChemoProteomics technologies to study #CovalentInhibitor target engagement at arginines.
A big thank you also to Stacey Paiva and her team at Nature Chemistry for their support and patience with me.
#CovalentInhibitor #DrugDiscovery #Proteomics #ChemicalProteomics #MassSpectrometry #Electrophiles #ProudPI #AcademicLife #NewPublication #Chemistry #ChemBio
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Stephan Hacker
Stephan Hacker