Development of XYD113 as a potent and highly selective GSPT1 degrader for cancer therapy.

G1 to S phase transition 1 (GSPT1) represents a promising yet historically challenging therapeutic target for MYC-driven malignancies. Herein, we identified XYD113, a potent and highly selective GSPT1-targeting molecular glue degrader. XYD113 exhibits significant antiproliferative activity (IC50 < 100 nM) against multiple MYC-overexpressing cancer cell lines (22Rv1, MV4-11, MOLM-16, Calu-1, HS-SY-II), and induces GSPT1 degradation in a dose- and time-dependent manner, with potency comparable to that of the clinical candidate MRT-2359. It also exhibits excellent selectivity without degrading common glutarimide analog substrates (such as SALL4, IKZF1/2/3, or CK1α). Mechanistically, XYD113 acts as a molecular glue to facilitate CRBN-GSPT1 ternary complex formation, mediating GSPT1 degradation via the UPS in a CRBN-dependent manner. Additionally, XYD113 demonstrates favorable stability in liver microsomes. Notably, XYD113 effectively downregulates the expression of genes critical for the initiation and progression of prostate cancer. In vivo, oral administration of XYD113 (5 mg/kg, daily for 21 days) significantly inhibited 22Rv1 xenograft growth (TGI = 46%) and showed a favorable safety profile in BALB/c-nude mice. Together, these findings highlight XYD113 as a promising therapeutic degrader worthy of further development for the treatment of MYC-driven cancers.