C7683

The primary reference demonstrates that C7683 is a potent, high-affinity (KD ~8–12 nM) small-molecule inhibitor of the E3 ubiquitin ligase Cbl-b, capable of stabilizing the protein both in vitro and in cells. Structural studies show that C7683 acts as an intramolecular glue, locking Cbl-b in an inactive conformation by binding at the interface of the TKBD and LHR domains, thereby preventing activation and supporting its use as a mechanistic tool compound. The chemical structure of C7683 matches 'compound No. 23' in Nurix Therapeutics' patent WO2020264398 and PubChem CID 155449671, and was revealed as the orally bioavailable Cbl-b inhibitor NX-1607 at the 2024 ACS spring meeting. While C7683 represents one of the best chemical probes currently available for Cbl-b, its cellular selectivity remains undisclosed and the specificity window is not fully defined, so concentrations for experimental use in cellular and in vivo assays should be chosen with this consideration.

The compound shows a very high potency when binding to Cbl-b in vitro. Cellular target engagement in HEK293 is convincintly demonstrated. However, data on toxicity, specificity and cellular target saturation are not available in the cited publication. The compound should thus be used with care. C7683 is a very close analogue of the clincal candidate Nx-1607 for which many more data is available. The citated publication does not specify the chemical difference to Nx-1607 and they are sold under the same CAS number. Researchers should be careful to not mix them up.