ArticleCommunications biology2023
The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition.
Article in Communications biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 30 citations in OpenAlex.
- Trial
- Pushing the boundaries of virtual screening scale of combinatorial spaces with the V-SYNTHES approach.npj drug discovery · 2026Article
- Optimization andACS medicinal chemistry letters · 2026Article
- Optimization Leading to a Potent and Selective Cbl‑b Inactive-State Inhibitor That DemonstratedACS medicinal chemistry letters · 2026Article
- Degrons and degradation signals beyond short linear motifs.Nature chemical biology · 2026Review
- A c-Cbl/Cbl-b antagonist inhibits EGFR ubiquitylation and sustains EGFR phosphorylation to enhance corneal re-epithelialization.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- NX-1607: lifting the Cbl-b brake to promote T cell activation through MAPK/ERK pathways.Journal for immunotherapy of cancer · 2025Article
- Molecular glues that inhibit deubiquitylase activity and inflammatory signaling.Nature structural & molecular biology · 2025Article
- Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- Cbl-b inhibitor NX-1607 activates MAPK/ERK signaling pathway and enhances T-cell activation.Journal for immunotherapy of cancer · 2025Article
- Molecular glues that inhibit deubiquitylase activity and inflammatory signalling.bioRxiv : the preprint server for biology · 2024Article
- Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.ACS medicinal chemistry letters · 2024Article
- The role of CBL family ubiquitin ligases in cancer progression and therapeutic strategies.Frontiers in pharmacology · 2024Review
- Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.ACS medicinal chemistry letters · 2023Article
- Small molecule inhibitors for cancer immunotherapy and associated biomarkers - the current status.Frontiers in immunology · 2023Review
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound's interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.