- Novel RBM39 molecular glue achieves complete tumor regression in mechanism-based Ewing sarcoma models; IND filing expected mid-2025
- Dual PROTAC strategy overcomes hook effect and enhances KRAS G12D degradation in collaboration with University of Pennsylvania
KING OF PRUSSIA, Pa., May 05, 2025 (GLOBE NEWSWIRE) — SEED Therapeutics Inc. (“SEED”), a biotechnology company pioneering targeted protein degradation (TPD) through discovery of novel molecular glues and bifunctional degraders, presented breakthrough research from two of its pipeline programs at the 2025 Annual Meeting of the American Association for Cancer Research (“AACR”), held April 27–30, 2025, in Chicago, Illinois. SEED’s proprietary RITE3
Novel RBM39 Degrader Demonstrates Complete Tumor Regression in Mechanism-based Ewing Sarcoma Models
RBM39 is an RNA-binding motif protein overexpressed in multiple cancers. Leveraging deep expertise in ubiquitin biology and E3 ligase structure, SEED developed a novel RBM39 degrader with significant potential to address the urgent need for new therapies in Ewing sarcoma (ES), an aggressive pediatric cancer with limited effective treatment options.
At AACR, SEED reported the following findings:
- ST-00937 degrades RBM39 to undetectable levels in A673 Ewing sarcoma cells, both in vitro and in vivo;
- Treatment with ST-00937 leads to complete elimination of established A673 tumors within two weeks;
- Mechanistic studies demonstrate that ST-00937 impairs homologous recombination repair pathways in A673 cells.
SEED expects to file an Investigational New Drug (IND) application for its next-generation RBM39 degrader, derived from ST-00937, in mid-2025. The program has been granted Rare Pediatric Disease and Orphan Drug designations by the U.S. Food and Drug Administration (FDA) (Press Release Link).
“We are proud of the rapid advancement of our potentially best-in-class RBM39 degrader toward clinical trials,” said Lan Huang, Ph.D., Co-Founder, Chair, and CEO of SEED Therapeutics. “Our clinical development strategy targets mechanism-driven indications, including liver cancer, KRAS-mutant cancers, and Ewing sarcoma. We are honored to collaborate with leading cancer centers such as Dana-Farber, Memorial Sloan Kettering, and MD Anderson as we move into clinical testing.”
Dual PROTAC Approach Overcomes Hook Effect and Advances KRAS G12D Degradation
The second presentation at AACR highlighted a novel bifunctional degrader strategy that combines two PROTACs using two E3s targeting KRAS G12D, addressing a major limitation in monotherapy PROTAC treatments known as the “hook effect“—the loss of degradation efficacy at high drug concentrations due to excessive binary complex formation.
Key findings presented include:
- 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 and promote apoptosis in pancreatic cancer models;
- The two-PROTAC combination effectively releases the hook effect, restoring degradation efficiency at higher doses;
- Synergistic effects were also observed in targeting the androgen receptor, suggesting broader applicability across disease-causing proteins.
“In combining two PROTACs using different E3 ligases to eliminate the hook effect, we pursued an unanticipated observation that led to a groundbreaking finding,” said James Tonra, Ph.D., President and Chief Scientific Officer of SEED Therapeutics. “We are grateful to collaborate with Professor Luca Busino at the University of Pennsylvania and excited to share this new strategy with the broader scientific and drug development community to realize its clinical potential.”
SEED Therapeutics Presentations at AACR 2025:
- AACR Poster 397
Title: Combinatorial Use of VHL- and KEAP1-based PROTACs Reveals Unexpected Synergy and Hook Effect Relief
Authors: Sehbanul Islam, Haihong Jin, Dong Liu, Dan Lu, Yunkai Zhang, Renxu Chang, Joel Austin, Thomas Beer, Hsin-Yao Tang, Lan Huang, James Tonra, Luca Busino
Session: Degrader and Glues 1
Abstract Control Number: 2582 - AACR Poster 7035
Title: Targeting Ewing Sarcoma with a Novel RBM39 Degrader: DNA Damage Repair Pathway Effects
Authors: Fei Liu, Yunkai Zhang, Baiyun Wang, James Finn, James Tonra, Lan Huang, Dong Liu, Haihong Jin, Xing Liu, Dan Lu
Session: Advances in Translational Pediatric Cancer Research
Abstract Control Number: 1556
About SEED Therapeutics
SEED Therapeutics is a biotechnology company pioneering targeted protein degradation (TPD) through the discovery of novel molecular glues and bifunctional degraders. Powered by its proprietary RITE3
Investor Contact: IR@seedtherapeutics.com
Media Contact: PR@seedtherapeutics.com
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