Developing Ubiquitin Ligase Agonists as Cancer Therapeutics

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DESCRIPTION (provided by applicant): The goal of this proposal is to develop a new concept in cancer therapy: to identify small molecules that restore the function of ubiquitin ligases that are mutated in cancers. The ubiquitin-proteasome system (UPS) targets proteins for degradation and controls many biological processes. Misregulated UPS activity has profound physiologic consequences and contributes to the pathogenesis of many diseases, including cancer. Tumors often contain mutations in ubiquitylation enzymes that either enhance or disable UPS function, depending on the affected gene. The UPS is thus an important therapeutic target in cancer and UPS inhibitors have already impacted clinical care. However, all current therapeutic approaches involve UPS inhibition, which cannot be applied to oncogenic mutations that disable protein degradation. Indeed, several key tumor suppressors are ubiquitylation enzymes that are inactivated by mutations in cancer. In many cancers, missense mutations reduce the binding affinity between ubiquitylation enzymes and their protein targets, and this allows oncogenic substrates to accumulate and drive carcinogenesis. These mutations also provide a unique opportunity for a novel therapeutic intervention, and we propose to develop small molecules that restore function to mutant ubiquitylation pathways in cancers. The Fbw7 F-box protein is the substrate receptor of an SCF ubiquitin ligase that degrades critical oncoproteins. Fbw7 is one of the most commonly mutated human tumor suppressors, and these mutations often involve missense mutations that prevent substrate binding. Based on our finding that a plant hormone, auxin, functions as a natural small-molecule agonist that increases the binding of a related ubiquitin ligase to substrates, we seek to identify small molecules that restore binding affinity to mutant Fbw7 proteins in cancers. We will use a rigorously characterized high-throughput screening platform to identify agonists that increase the binding of tumor-derived Fbw7 proteins to substrates. We have also developed a unique array of biochemical and physiologic validation assays, as well as structural and medicinal chemistry approaches for compound development. If successful, this research will establish a new paradigm of drug therapy that targets defective protein degradation pathways. Importantly, our work's impact will extend beyond Fbw7, and facilitate similar approaches that target ubiquitylation pathways related to Fbw7 that are also mutated in cancers.