SEED Therapeutics Inc., a biotechnology company focused on targeted protein degradation (TPD), presented groundbreaking research from two pipeline programs at the 2025 American Association for Cancer Research (AACR) Annual Meeting in Chicago. The presentations highlighted significant advances in the company's proprietary RITE3SM platform for developing molecular glues and bifunctional degraders targeting previously undruggable proteins.
Novel RBM39 Degrader Shows Promise for Ewing Sarcoma
SEED's lead program, a novel RBM39 degrader designated ST-00937, demonstrated remarkable efficacy in Ewing sarcoma models. RBM39, an RNA-binding motif protein overexpressed in multiple cancers, has emerged as a promising target for this aggressive pediatric cancer that currently has limited treatment options.
The research presented at AACR revealed that ST-00937 degrades RBM39 to undetectable levels in A673 Ewing sarcoma cells both in laboratory studies and animal models. Most impressively, the treatment led to complete elimination of established A673 tumors within two weeks.
"Our potentially best-in-class RBM39 degrader represents a significant advancement in targeted protein degradation for cancer treatment," said Dr. Lan Huang, Co-Founder, Chair, and CEO of SEED Therapeutics. "We're particularly encouraged by the mechanistic studies demonstrating that ST-00937 impairs homologous recombination repair pathways in cancer cells."
The company plans to file an Investigational New Drug (IND) application for its next-generation RBM39 degrader, derived from ST-00937, by mid-2025. The program has already received both Rare Pediatric Disease and Orphan Drug designations from the U.S. Food and Drug Administration (FDA).
SEED's clinical development strategy targets mechanism-driven indications beyond Ewing sarcoma, including liver cancer and KRAS-mutant cancers. The company has established collaborations with leading cancer centers including Dana-Farber, Memorial Sloan Kettering, and MD Anderson for upcoming clinical trials.
Innovative Dual PROTAC Approach Overcomes "Hook Effect"
In a separate presentation, SEED highlighted a novel bifunctional degrader strategy that combines two PROTACs (Proteolysis Targeting Chimeras) using different E3 ligases to target KRAS G12D, a notoriously difficult-to-drug oncogenic mutation.
This innovative approach addresses a major limitation in PROTAC therapies known as the "hook effect" – the loss of degradation efficacy at high drug concentrations due to excessive binary complex formation. The research, conducted in collaboration with Dr. Luca Busino's laboratory at the University of Pennsylvania, demonstrated that:
- VHL-based PROTACs targeting KRAS G12D display the classic hook effect at high concentrations
- KEAP1-based PROTACs synergize with VHL-based PROTACs to enhance KRAS G12D degradation
- The two-PROTAC combination effectively releases the hook effect, restoring degradation efficiency
- The combination promotes apoptosis in pancreatic cancer models
- Similar synergistic effects were observed when targeting the androgen receptor, suggesting broader applicability
"In combining two PROTACs using different E3 ligases to eliminate the hook effect, we pursued an unanticipated observation that led to a groundbreaking finding," explained Dr. James Tonra, President and Chief Scientific Officer of SEED Therapeutics. "This strategy has potential applications across multiple disease-causing proteins."
Dr. Busino added, "Our team's research experimentally demonstrated anticancer synergy between two PROTACS using different E3 ligases to target the same oncogene and kill cancer cells. We're excited to share this data on superior degradation efficacy against KRAS G12D, a long-targeted oncogene."
Expanding the Frontier of Targeted Protein Degradation
SEED Therapeutics is rapidly establishing itself as a leader in the targeted protein degradation field. The company's proprietary RITE3SM platform enables the discovery of first-in-class degraders for traditionally undruggable targets across multiple therapeutic areas, including oncology, neurodegeneration, immunology, and virology.
The company has secured strategic collaborations with pharmaceutical giants Eli Lilly and Company and Eisai Co., Ltd. to support its mission of developing transformational therapies.
As SEED transitions toward becoming a clinical-stage company with its planned IND filing, these presentations at AACR 2025 demonstrate the company's commitment to pioneering science and rational drug development in the rapidly evolving field of targeted protein degradation.
The abstracts and posters presented at AACR are available on the AACR website, providing detailed scientific data on both breakthrough programs.
