ILLUMINATING THE "DARK MATTER" OF PHARMACOLOGY: EMERGING STRATEGIES TO TARGET UNDRUGGABLE AND UNCHARACTERIZED BIOLOGICAL TARGETS

Background: A large share of the proteins that matter most in human disease have never yielded to ordinary small-molecule chemistry. The reasons are structural rather than biological: some of these proteins simply have no deep cavity for a ligand to occupy, others flex between many shapes or remain partly unfolded, and a great many do their work through wide contact surfaces with partner proteins instead of through a single catalytic site. A further group has barely been characterised at all, so there is no clear picture of what a drug would need to do.[2] Emerging modalities and advances. It is more useful to read this collection of intractable proteins — the pharmacological “dark matter” — as unfinished business than as a fixed limit on what medicinal chemistry can reach. Over the past decade the toolkit has widened considerably: proteins can now be destroyed rather than merely blocked, glued to unintended partners, engaged covalently or from a distance through regulatory sites, probed with small fragments, silenced at the level of their transcripts, or intercepted with peptides and biologics. Structural biology and machine learning have accelerated all of these routes.[2] What unites them is that none depends on the classical recipe of a well-shaped orthosteric pocket; each instead makes use of something else the target offers — a fleeting cavity, an exposed surface, an interaction interface, a route into a degradation pathway, or the nucleic-acid sequence that encodes it.[2] Clinical relevance and case examples. KRAS is the clearest demonstration that “undruggable” is a statement about available methods and not about the protein. Covalent chemistry aimed at a mutant cysteine, and later non-covalent recognition of a different mutant, converted a target that had frustrated the field for three decades into one with approved and advancing medicines.[8] Targeted degradation has made a parallel point from the opposite direction, clearing proteins from the cell that were never plausible candidates for occupancy-based inhibition.[3] Conclusion and outlook. This review draws together the principal strategies now being applied to hard targets, the classes of protein each strategy suits, what each buys and what it costs, and the steps still needed before poorly characterised biology can be turned into medicines.[2]