NX-1607

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 convincingly demonstrated. The compounds appears not be toxic, and shows target-dependent cellular effects with EC50 values just below 1 uM. However, data on compound specificity and cellular target saturation are not available in the cited publications. C7683 and the Nurix clincal candidate Nx-1607 are the same molecule. The available data support the use of C7683/Nx-1607 as a tool compound to interrogate the function of the Cbl-b E3 ligase.