CC-90009 exerts potent anti-JEV activity both in vitro and in vivo by inducing proteasomal degradation of the GSPT1/NS5 complex, thereby disrupting viral translation and replication. This targeted protein degradation strategy represents a novel host-directed antiviral approach with promising therapeutic potential against mosquito-borne viral encephalitis.

P1, N=10, Not yet recruiting, Pfizer

The results of the phase III VERITAC-2 study, comparing vepdegestrant with fulvestrant, are expected to be available in 2025, and will provide the first data on the true clinical significance of vepdegestrant. Several phase III studies of combinations with vepdegestrant including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) have been or are planned to be conducted. The results of these may not only transform the treatment landscape for advanced HR+/HER2- breast cancer but may pave the way for PROTAC as a new class of anti-cancer drugs that may make previously undruggable targets druggable.

P1/2, N=11, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=67 --> 11 | Trial completion date: Jan 2027 --> Nov 2025 | Trial primary completion date: Jul 2026 --> Nov 2025

P1, N=9, Completed, Pfizer | Active, not recruiting --> Completed

These findings suggest a new role of GSPT1 in regulating leukemic transcriptional networks and open a new therapeutic strategy to target leukemic fusion genes in pediatric AML patients.

Importantly, 7d exhibits superior efficacy compared to 1 (CC-90009) in degrading GSPT1 in 22Rv1 cells with a DC50 value of 19 nM...Mechanistically, via degradation of GSPT1, 7d downregulates CRPC-related oncogenes in 22Rv1 cells, including AR, AR-V7, PSA, and c-Myc. Thus, our work provides a novel GSPT1 selective degrader with potent effectiveness in targeting Myc-driven CRPC.

Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.

P1, N=12, Recruiting, Pfizer | Not yet recruiting --> Recruiting

ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471...Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer.

P3, N=624, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

Vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer with no notable differences in pharmacokinetics from Western patients.