Nondegradative Synthetic Molecular Glues Enter the Clinic

Molecular glues are small molecules that can induce or stabilize protein-protein interactions between proteins inside cells. Unlike classical small molecule drugs, molecular glues can target challenging disease-causing proteins lacking well-defined binding pockets. Nature has repeatedly used this mode of action, but identifying molecular glues for new target proteins has been a major challenge. Recently, manmade molecular glues, inspired by natural products, for KRas, entered clinical trials although KRas is a major cancer target long thought to be undruggable. Here, how these molecules are initially discovered and optimized to provide several advanced drug candidates for various KRas-dependent cancer types are outlined. The major insights obtained for this new class of drug modalities are further summarized. These results showcase how molecular glues that do not rely on protein degradation can provide clinical benefits for challenging drug targets.