LAUSR

Description Small-molecule degraders of SUMO1 induce its ubiquitination and degradation through binding of CAPRIN1 in tumor cells in vitro and in vivo. Degrading the undruggable Ubiquitination controls degradation of proteins and is an enticing therapeutic strategy for treating cancer by degrading oncoproteins that cannot be targeted with small molecules. One prospective target is SUMO1, which modifies oncoproteins through sumoylation that contribute to oncogenesis and metastasis. Here, using a cancer cell-based small-molecule screen for compounds that degrade SUMO1, Bellail et al. identified CPD1. By improving the potency and pharmacokinetics of CPD1, the researchers created a lead compound HB007. HB007 was able to induce ubiquitination and degradation of SUMO1, resulting in reduced tumor growth in multiple patient-derived xenograft mouse models. This approach could be applied to identify other small-molecule degraders for cancer therapy. Discovery of small-molecule degraders that activate ubiquitin ligase–mediated ubiquitination and degradation of targeted oncoproteins in cancer cells has been an elusive therapeutic strategy. Here, we report a cancer cell–based drug screen of the NCI drug-like compounds library that enabled identification of small-molecule degraders of the small ubiquitin-related modifier 1 (SUMO1). Structure-activity relationship studies of analogs of the hit compound CPD1 led to identification of a lead compound HB007 with improved properties and anticancer potency in vitro and in vivo. A genome-scale CRISPR-Cas9 knockout screen identified the substrate receptor F-box protein 42 (FBXO42) of cullin 1 (CUL1) E3 ubiquitin ligase as required for HB007 activity. Using HB007 pull-down proteomics assays, we pinpointed HB007’s binding protein as the cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1). Biolayer interferometry and compound competitive immunoblot assays confirmed the selectivity of HB007’s binding to CAPRIN1. When bound to CAPRIN1, HB007 induced the interaction of CAPRIN1 with FBXO42. FBXO42 then recruited SUMO1 to the CAPRIN1-CUL1-FBXO42 ubiquitin ligase complex, where SUMO1 was ubiquitinated in several of human cancer cells. HB007 selectively degraded SUMO1 in patient tumor–derived xenografts implanted into mice. Systemic administration of HB007 inhibited the progression of patient-derived brain, breast, colon, and lung cancers in mice and increased survival of the animals. This cancer cell–based screening approach enabled discovery of a small-molecule degrader of SUMO1 and may be useful for identifying other small-molecule degraders of oncoproteins.