c-Myc- and KRas-dependent cancers, such as colorectal cancer, represent major unmet medical needs that currently lack targeted therapy. Recent scientific advances revealed that these ?undruggable? oncogenes critically depend on post-translational modification with the small ubiquitin-like modifier (SUMO) family of proteins, and inhibiting SUMOylation inhibits c-Myc and KRas. Furthermore, SUMOylation inhibition can activate anti-tumor immune responses. Genome- wide gene expression analysis has demonstrated that the SUMO activating enzyme (E1) is the most overexpressed SUMOylation-related protein in colorectal cancers tissues. SUMO E1 overexpression is also associated with cancer cell stemness and poor patient survival. This evidence makes SUMO E1 an attractive target. Therefore, we propose to develop highly selective, potent, and orally available SUMO E1 inhibitors as targeted therapies for colorectal cancer. Using a high-throughput screening campaign, we have identified a class of potent and specific SUMO E1 inhibitors suitable for development into orally available drugs, which could represent a new class of therapeutic agents. We will conduct lead optimization of these compounds and validate the resulting candidates in cellular assays of colorectal cancer, followed by pharmacokinetic and toxicity studies. In addition to colorectal cancer, which is the focus of our proposal, inhibiting SUMOylation will likely inhibit other c-Myc and KRas-dependent cancers. Thus, the potent SUMO E1 inhibitors developed in the proposed studies are expected to have a major impact on cancer research and targeted therapy.
