Ubiquitination and degradation of SUMO1 by small-molecule degraders extends survival of mice with patient-derived tumors

Abstract

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.

Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy

“…Here, we showed compelling evidence that USP7 downregulated cells became less sensitive to EB inhibition. On the basis of previous reports (43)(44)(45), we speculate a possible mechanism that USP7 knockdown causes an obviously reduced expression in the cellular target of EB (target-ligand interaction metrology), thereby leading to a weakening effect of EB on the USP7-associated downstream inflammation signaling pathway. This may explain the reason for the impaired anti-inflammation effect of EB upon USP7 knockdown in our study.…”

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“…HB007 inhibits the proliferation of various tumor cells by selectively degrading SUMO1. 1068 The highly selective SAE inhibitor TAK‐981 can significantly upregulate the expression of IFN1 and activate IFN1‐dependent innate immune cells, including macrophages, NK cells, DCs, and T cells, promoting antitumor immune responses. 1069 Moreover, TAK‐981 is currently in phase 1 clinical trials in patients with solid tumors and lymphomas.…”

“…Further druggability optimization identifies the first highly selective SUMO1 degrader, HB007. HB007 inhibits the proliferation of various tumor cells by selectively degrading SUMO1 1068 . The highly selective SAE inhibitor TAK‐981 can significantly upregulate the expression of IFN1 and activate IFN1‐dependent innate immune cells, including macrophages, NK cells, DCs, and T cells, promoting antitumor immune responses 1069 .…”

Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates?

“…To date, no modulator specifically targeting SUMO E3 enzymes has been reported. On the other hand, small-molecule degraders that induce the ubiquitination and degradation of patient tumor-derived grafts, inhibited cancer progression, and increased the survival of the animals (Bellail et al, 2021). Further investigations are necessary to determine if HB007 indeed functions as a molecular glue by determining the full-length CAPRIN1 structure and its complexes with HB007 and FBXO42, as well as to identify the structural basis of HB007's SUMO1 selectivity.…”