Chemical Biology Methods and Concepts that Redefine Druggability

Despite the successes of traditional drug discovery methods, certain proteins and diseases, were once considered “undruggable”. This description encapsulated the belief that certain proteins were unamenable to small molecule drug design. These coveted but unyielding targets were typically avoided by the drug discovery community. Recently, several new drugs have appeared, helping to rewrite what is “undruggable”.Arguably, the biggest breakthroughs have occurred by deploying chemical biology in drug design and development. Foundational examples include: novel screening approaches leading to RasG12C inhibitors; and rational design of drugs with new mechanisms, yielding protein degraders. Newer work is applying chemical biology to challenge our conception of “undruggable” even further. One key example is new induced dimerization paradigms, such as LYTACs and PhosTACs. This extends to new sensing and detection strategies, e.g., methods to assay and perturb cellular biophysical properties. Other examples include: proximity labeling methods to map protein-protein interactions and subcellular proteomes, such as TurboID; methods, like activity-based protein profiling, that can characterize pleiotropic, reactive drugs, like Tecfidera®, at the network and state levels; and network visualisation tools like MicroMap, an interface that depicts microbe metabolic networks at the systems level.These and similar approaches are poised to transform how we conceive and develop therapeutics. We are at a tipping point: chemical intuition is revolutionizing both drugs on the shelves and the development process itself. This is occurring because chemical biologists are designing revolutionary activity assays conferring the ability to decode mechanisms of multi-target drugs. They are also providing cutting-edge, yet user-friendly tools to control and measure a broad palette of cellular parameters. To reflect chemical biology’s pivotal role in advancing health, our overall goal is to create an issue geared towards: (1) discussing the medicinal chemistry milestones that chemical biology has reached recently. These are exemplified by approved drugs derived from novel assay development, e.g., RasG12C inhibitors; but we particularly encourage emerging areas, such as stabilizers of p53(Y220C). We are also interested in new drugs with unprecedented mechanisms entering phase III clinical trials, e.g., protein degraders, like PROTACs as well as mechanistically similar molecules, like LYTACs and other function-inducing molecules.(2) looking forward to how chemical biology can build on its success in revolutionizing druggability. This includes targeting non-peptide macromolecular structures, e.g. RNA or membranes and also new assays and delivery platforms. It also covers deployment of new chemical architectures, like transition metal complexes.We thus aim to concretize nascent trends in the deployment of chemical biology principles to drug discovery. We also hope to guide and inspire those of the future. Chemical biology harnesses chemistry’s ability to fashion molecular architectures to accessorize biological apparatuses. This field is revolutionizing therapeutic design and development. With chemical biology’s help, we have moved beyond activity blockers to molecules modulating biological function. These are exemplified by targeted degraders like PROTACs, as well as newer dimerization inducers, like LYTACs and PhosTACs. Complex screening platforms have also been constructed, leading to the discovery of RasG12C inhibitors and spurring molecules targeting other disease driving mutations, e.g. p53(Y220C). Chemical biology is also shaping concepts in drug design, through: mapping protein-drug or protein-protein interactions, e.g. Turbo-ID; and decoding functions of reactive, pleiotropic drugs, like Tecfidera®, by techniques like activity-based protein profiling and REX-technologies. To celebrate chemical biology’s coming of age, we aim to assemble an topic of Original Research, Perspectives, and (Mini)-Reviews showcasing how chemical biology is redefining “druggability”. We welcome submissions on:• chemical biology in drug-discovery, including: novel drug screening and discovery platforms; as well as drugs designed to reengineer their target’s functions.• the above areas deploying innovative imaging techniques, induced proximity, proximity mapping, or the use of transient intermediates.• targeting undruggable proteins through new mechanisms or molecular architectures.• targeting non-protein macromolecules, such as RNA or membranes.• methods to deconvolute pleiotropic molecules and processes.• historical perspectives on any of these areas.We hope this topic will inspire current chemical biologists and encourage researchers from diverse fields to contribute to shaping the future of drug discovery by adopting chemical biology concepts and techniques. Topic editors: Marcus Long, Yue Pan, Jesse R. Poganik Source: https://www.frontiersin.org/research-topics/77941/chemical-biology-methods-and-concepts-that-redefine-druggability