Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach

A single antibody fragment, smaller than a human hair’s width, is being used as a template to design new drug-like compounds that block a key cancer-driving protein. RAS proteins are mutated in roughly one in five human cancers, yet no approved drug directly targets them. The problem is that RAS is a smooth, featureless surface—conventional small-molecule drugs struggle to latch onto it. The researchers previously developed an antibody fragment that binds tightly to mutant RAS, but antibodies themselves make poor drugs because they cannot enter cells. This project uses that antibody fragment as a structural blueprint, screening thousands of chemical fragments to find small compounds that mimic the antibody’s binding action. If successful, the work could produce a new class of cancer drugs that directly disable mutant RAS inside cells. Because the approach targets the cancer-specific, GTP-bound form of RAS while sparing the normal, GDP-bound version, such compounds might offer fewer side effects than existing treatments. The research remains at an early, fundamental stage—the immediate goal is to identify hit compounds with the right binding properties, not to test them in patients. Similar structure-guided fragment screening has previously yielded drugs for other difficult targets, including HIV protease and certain kinases.