Talus Bio unveiled promising preclinical data for its novel transcription factor-targeting therapeutics at the American Association for Cancer Research (AACR) Annual Meeting held April 25-30, 2025. The Seattle-based biotechnology company presented compelling evidence supporting its innovative approach to modulating previously "undruggable" transcription factors in chordoma, non-small cell lung cancer (NSCLC), and advanced prostate cancer.
"We built our platform to systematically address transcription factors, a target class long considered out of reach for small-molecule therapeutics," said Alex Federation, PhD, CEO and Co-Founder of Talus Bio. "The data we're presenting at AACR show that the approach is working. Our platform has already logged over 50 million protein-compound interactions this year."
Transcription factors, proteins that regulate gene expression by binding to specific DNA sequences, have historically been challenging targets for drug development despite their critical role in disease pathways. Talus Bio's technology aims to overcome these challenges through its proprietary regulome sequencing platform.
TAL61 Shows Significant Efficacy in Chordoma and NSCLC Models
In a standout presentation, researcher Gaelle Mercenne showcased data on TAL61, a novel covalent small molecule designed to inhibit the transcription factor Brachyury. The compound demonstrated significant anti-tumor activity in patient-derived xenograft (PDX) models of chordoma, a rare bone cancer with limited treatment options.
Key findings for TAL61 included:
- Significant reduction in tumor burden in PDX chordoma models
- Durable tumor suppression that persisted after treatment cessation
- Low toxicity profile with high tolerability during daily dosing regimens
- More than 50% decrease in tumor burden in Brachyury-positive NSCLC models
These results are particularly noteworthy as Brachyury overexpression is implicated in both chordoma pathogenesis and the progression of certain NSCLC subtypes. Federation confirmed that the Brachyury-targeting molecules are "on track for candidate nomination," suggesting advancement toward potential clinical development.
Novel Approach for Metastatic Castration-Resistant Prostate Cancer
In another significant presentation, Brian McEllin detailed findings on compounds targeting NONO, a protein involved in transcriptional regulation in prostate cancer. The research demonstrated a novel therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC), a condition with poor prognosis and limited treatment options.
The NONO-targeting compounds showed promise by:
- Disrupting both androgen receptor (AR) and AR-V7 variant transcription
- Reducing mRNA and protein levels of AR and AR-V7 in prostate cancer cells
- Abrogating AR and AR-V7 gene expression programs in castration-resistant models
"New compounds targeting NONO and AR-V7 show real promise for metastatic castration-resistant prostate cancer," Federation noted. This approach could potentially address treatment resistance in advanced prostate cancer, where AR-V7 expression often drives resistance to current therapies.
Regulome Sequencing Platform: A Breakthrough Technology
The foundation of Talus Bio's approach is its regulome sequencing platform, which provides a quantitative readout of active transcription factors in live, unmodified human cells. Federation presented data highlighting the platform's capabilities as a drug discovery engine.
The technology offers several key advantages:
- Quantitative, time-resolved measurement of drug-induced changes in transcription factor activity
- Simultaneous capture of protein-genome interactions for thousands of proteins
- Physiologically relevant screening contexts that maintain natural transcription factor function
- AI-guided hit discovery and optimization
"This approach enables small molecule screening in physiologically relevant contexts, where transcription factors fold, assemble, and function as they do in human disease," explained Federation. The platform can measure over 10,000 regulomes monthly, accelerating the discovery process for transcription factor modulators.
Expanding Pipeline and Future Directions
Talus Bio's foundational AI model has helped identify over 30 tractable compounds against validated transcription factor targets in cancer and other diseases. Beyond Brachyury and NONO, the company has also made progress on inhibitors for STAT3, another challenging transcription factor target.
"We now have a repeatable model for discovering tractable starting points across transcription factor targets once thought undruggable," Federation stated, highlighting the broader implications of their technology platform.
Founded in 2020 by Federation and Lindsay Pino, PhD, Talus Bio is actively pursuing co-development opportunities with partners to accelerate these discoveries into clinical trials. The company continues to build its team of experts in proteomics, chemistry, and machine learning to advance its pipeline of transcription factor-targeted therapies.
Implications for Cancer Treatment
The data presented at AACR 2025 represent significant progress in addressing a longstanding challenge in drug development. By successfully targeting transcription factors that were previously considered undruggable, Talus Bio's approach could potentially open new avenues for treating cancers with high unmet medical needs.
For patients with chordoma, a rare cancer with limited treatment options, the Brachyury-targeting compounds could represent a first-in-class therapeutic approach. Similarly, for patients with metastatic castration-resistant prostate cancer who have exhausted current treatment options, the NONO-targeting strategy offers a novel mechanism to overcome resistance.
As the company advances these programs toward clinical development, the oncology community will be watching closely to see if these promising preclinical results translate into effective therapies for patients with difficult-to-treat cancers.
