DDD2 is a selective and efficient VHL-mediated PROTAC degrader specifically targeting NUDT5. It effectively induces substantial degradation of NUDT5. DDD2 consists of the warhead TH10184 and the VHL-recruiting ligand VH032, connected via a saturated aliphatic eight-carbon linker. DDD2 is applicable in cancer research, including studies on lymphocytic leukemia and osteosarcoma.

DDD2, at a concentration of 2 µM for 24 hours, induces significant NUDT5 degradation in U-2 OS cells. In CCRF-CEM cells, DDD2 (concentration range of 0.01-10 µM for 4-96 hours) also triggers endogenous NUDT5 degradation in a concentration- and time-dependent manner. Degradation of NUDT5 by DDD2 at 1 µM for 24 hours in U-2 OS cells depends on VHL rather than CRBN. DDD2 demonstrates good solubility and stability, with an average kinetic solubility of 6.25 µM.