undruggable

Undruggable is a term used in pharmacology to describe biological targets, most often proteins, that have resisted modulation by conventional small-molecule drugs or biologics. In drug discovery, an undruggable target is typically characterized by the absence of deep, well-defined binding pockets on its surface, essential enzymatic activity, or critical roles in disease that do not translate to easily interrupted function. Targets such as certain transcription factors, scaffolding proteins, and protein–protein interaction interfaces have historically been labeled undruggable.

The concept arose as many disease-relevant proteins lacked druggable features; examples include MYC and p53. For decades KRAS was also considered undruggable until mutation-specific covalent inhibitors emerged, demonstrating that alternative binding modes or contexts can enable drug discovery.

Challenges include flat surfaces, disordered regions, difficulty achieving selectivity and cell permeability for larger biologics, and the need to influence protein interactions rather than enzymatic activity.

Advances show that undruggable is a moving target: covalent inhibitors, allosteric modulators, targeted protein degradation (PROTACs), molecular glues, and other strategies have enabled modulation of previously intractable proteins. Notable progress includes KRAS G12C inhibitors such as sotorasib and adagrasib, and the broader use of PROTACs to degrade target proteins.

Despite progress, not all undruggable targets are now druggable; many challenges remain, and success is highly target-specific.

In current discourse, undruggable is often used descriptively, with recognition that drug discovery methods continue to expand what can be modulated.