Advances in Chemical Probing Concepts for Chemical Biology Applications

Chemical probes allow us to identify, validate and confirm novel targets for therapeutic applications, enable the development of drug candidates, and open the way to new therapeutic strategies, vaccines and diagnostic tools. Chemistry at the interface of biology is playing an increasingly important role in biomedical science, facilitating new cutting-edge technologies to understand biology and discover new treatments for human diseases.1 The concept of “chemical genetics” recognizes the power of bioactive molecules as tools to study biological processes.2 In analogy to genetic perturbations, forward and reverse chemical genetics approaches can be distinguished. In forward chemical genetics, the phenotypic changes in cellular systems after exposure to small molecules are studied, with the aim of identifying the underlying target and pathway biology (target agnostic approach). In reverse chemical genetics, a compound with specific activity for a particular known target is used to study the phenotypic consequence of target modulation (approach focused on protein of interest). The development of chemical reactions that proceed in living systems without compromising the biochemical integrity of the system under study (bioorthogonal chemistry) has been a breakthrough for chemical genetics approaches (2022 Nobel Prize in Chemistry).3 Bioorthogonal chemistry has enabled a broad range of biomolecules (glycans, proteins, lipids, nucleic acids) to be probed in biological systems at various levels of complexity (cells, tissues and animals) with excellent biocompatibility. Chemical biology has gained significant importance for the deconvolution of novel druggable targets from “omics” approaches and phenotypic screening technologies, opening the field of chemoproteomics.4 Revealing and characterizing novel putative drug targets is the foundation of chemical probe-based drug discovery, which complements the “classical” phenotypic and target-based approaches. The power of combining “omics” approaches and chemical probing to expand druggable space is exemplified by the breakthrough discovery of KRAS G12 C inhibitors—a target considered to be undruggable for decades—such as Sotorasib and Adagrasib, FDA-approved in 2021 and 2022, respectively. Dedicated research into chemical probes as tool compounds in biomedical research has led to the definition of specific profiles for chemical probe versus drug molecules.5 High-quality and high-impact probes are designed for the biological hypotheses or questions asked in a drug discovery context, and may be inspired by known ligands of a given target. Functionalization of these probes with non-drug-like moieties, such as click moieties, reactive groups (e. g., warheads), photocages, photoswitches, protein-tags, degradation-tags or fluorescent dyes enables probes to be used in multiple contexts. Thus, advances in chemical probe concepts gain more and more importance for detailed studies of physiological and molecular processes, helping to address challenges in medicine, including emerging infectious diseases, antimicrobial resistance, cardiovascular diseases, neurosciences or cancer. In summary, biomedical research approaches leveraging chemical probes allow the identification, validation and confirmation of novel targets for therapeutic applications, enable the development of drug candidates, and open the way to new therapeutic strategies, vaccines and also diagnostic tools. This Special Collection highlights the role of chemical probes in biomedical discovery today and aims to identify emerging trends and technologies in the discovery of the next wave of drug targets that will advance medical progress in the next decade. After a training in chemistry at the University of Pisa, Italy, Dr Paola B. Arimondo obtained a PhD in biophysics at the MNHN, Paris, and a PhD in chemistry at the Scuola Normale Superiore of Pisa. She is research director at the CNRS, head of the Epigenetic Biological Chemistry Unit the Department of Structural Biology and Chemistry of the Institut Pasteur and the CNRS-Institut Pasteur UMR 3523 Chem4Life in Paris, France. Her research activities focus on the epigenetic regulation and its targeting with chemical molecules to fight diseases. Before joining the Institut Pasteur, she directed the Epigenetic Targeting of Cancer (ETaC) unit, a joint public-private laboratory between the CNRS and Pierre Fabre Laboratories, in Toulouse, France. Sebastian Essig studied chemistry and biology at the University of Heidelberg, Germany, and obtained his PhD in organic chemistry in 2013. Subsequently, he joined the group of Prof. Jason Chin at the MRC Laboratory of Molecular Biology in Cambridge, UK, where he completed his postdoctoral training in chemical biology and synthetic biology. In 2016, he started at Bayer AG as a medicinal chemist where he was involved in different drug discovery programs. He is currently Director of Chemical Biology in Bayer's Life Science Technology Department focusing on chemoproteomics methods, covalent chemistry, novel target discovery and deconvolution strategies. Arne C. Rufer received his doctoral degree in biochemistry from the University of Cologne. He solved the crystal structure of the diabetes target carnitine palmitoyltransferase in close collaboration with F. Hoffmann-La Roche. During his postdoc at the Max Planck Institute for Medical Research, he used biophysical methods to characterize binding modes of adaptor proteins. After returning to F. Hoffmann-La Roche, he continued to link biochemical and biophysical approaches for target assessment, lead identification, and lead optimization in various roles. He founded a Mechanistic Enzymology group and is now Senior Principal Scientist and Section Head in the Lead Discovery department. Ulrich Schopfer is the head of Chemical Biology & Therapeutics at the Novartis Institutes for BioMedical Research (NIBR) in Basel/Switzerland. The department applies chemical biology, data science and enabling technologies to discover novel targets, to prototype new drug modalities and to contribute drug candidates to the Novartis pipeline. Throughout his career, Ulrich has been intrigued by the relationship between molecular structure and biological function. Obtaining a PhD in organic chemistry for work on conformational design of bioactive molecules with R. W. Hoffmann in Marburg/Germany, he pursued postdoctoral work with R. Noyori at Nagoya University/Japan followed by a visiting scholar year working on artificial zinc finger transcription factors with C. F Barbas at The Scripps Research Institute in La Jolla/USA.