Probing the mechanism of Cbl-b inhibition by a small-molecule inhibitor
Kimani, S.; Perveen, S.; Szewczyk, M.; Zeng, H.; Dong, A.; Li, F.; Ghiabi, P.; Li, Y.; Chau, I.; Arrowsmith, C.; Barsyte-Lovejoy, D.; Santhakumar, V.; Vedadi, M.; Halabelian, L.
Show 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, and Nx-1607, is in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirmed 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 compound 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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