UNC10088 is a molecular glue that targets NSD2. It facilitates the formation of a stable ternary complex between SCFFBXO22 and the NSD2 PWWP1 domain. UNC10088 binds reversibly and covalently to the C326 of FBXO22, promoting the ubiquitination of the NSD2 PWWP1 domain in an SCFFBXO22-dependent manner. UNC10088 can be utilized in cancer research.

UNC10088, at a concentration of 0.5 μM for 15 minutes, interacts with the C326 residue of FBXO22, facilitating the formation of a stable ternary complex. This interaction drives SCF FBXO22-dependent polyubiquitination of the NSD2 PWWP1 domain. The process relies on specific interaction residues such as E362, K229, and E169 of FBXO22, and F266, E272, and K253 of NSD2, where mutations can disrupt complex stability or degrader localization and inhibit ubiquitination. When UNC10088 is used at 5 μM for 1 hour, its binding to the FBXO22 FIST domain is strictly dependent on Cys326, as a C326A mutation abolishes complex formation, but reintroducing cysteine into a cysteine-deficient background restores complex formation. Addition of FBXO22 reduces the IC50 of UNC10088 by 2.5 times (from 248 nM to 101 nM), indicating positive cooperative binding with an α factor of 3.3. UNC10088 significantly increases the melting temperature (Tm) of the FIST domain in wild-type FBXO22; however, it has little effect on the Tm of the C326A mutant.