LAUSR

The Ras family of GTPases and are important but poorly druggable therapeutic targets that are frequently mutated in cancer. In this issue of ACS Central Science, Lim et al. present the development of a panel of biodegraders that trigger rapid degradation of endogenous K-Ras proteins with conformational specificity. The Ras GTPases (K-Ras, H-Ras, and N-Ras) cycle between the active GTP-bound state, which interacts with downstream effectors to promote cell growth, differentiation, and survival, and the inactive GDP-bound state. Activating mutations in Ras proteins are prevalent oncogenic drivers in a number of tumor types including pancreatic ductal adenocarcinoma (K-Ras), head and neck squamous cell carcinoma (H-Ras), and cutaneous melanoma (N-Ras). Small-molecule Ras inhibitor development is challenging due to the picomolar affinity these enzymes have for guanine nucleotides, which are present at high concentrations in the cell (0.1−1 mM) and compete with inhibitors for active site binding. Covalent inhibitors of the K-Ras mutant have shown promise in nonsmall cell lung cancer patient trials and provide clinical validation of K-Ras inhibition. However, other Ras mutants that lack a reactive cysteine proximal to the active site remain undrugged despite intensive efforts in the medicinal chemistry community. Targeted protein degradation (TPD) has emerged as a new paradigm in drug discovery which circumvents the need for high target occupancy. Here, a heterobifunctional small molecule (degrader) recruits a protein of interest (POI) to an E3-ubiquitin ligase. The induced proximity results in the ubiquitination of the POI, and its subsequent proteasomal degradation. Limitations of TPD include the requirement for small-molecule binders of the target protein and E3 ligase of interest, and the unknown compatibility of the target:E3 ligase pair. A number of chemical genetic strategies have been developed to enable targeted protein degradation of unliganded proteins including K-Ras. These approaches use a second protein as a degradation tag, and a tag-directed degrader to recruit an E3-ligase to a POI-tag fusion chimera. However, appendage of a proteintag may alter the activity, interactome, or localization of a POI, and current tag-based approaches are limited by their inability to target endogenous proteins. Similarly, varying the recruited E3 ligase can alter the degradation efficacy of a tagged POI.