Parabilis Medicines has unveiled groundbreaking preclinical data demonstrating the first successful targeted degradation of ERG, a transcription factor implicated in 40-50% of prostate cancers, at the American Association for Cancer Research (AACR) Annual Meeting in Chicago.
The Cambridge, Massachusetts-based biopharmaceutical company presented compelling evidence showing potent degradation of ERG across three mouse models of ERG-fusion prostate cancer, correlating with substantial tumor growth inhibition. This represents the first pharmacological proof-of-concept for ERG dependency in preclinical models of ERG-fusion prostate cancer.
"Parabilis's Helicon peptide degraders have thrilling potential to expand the reach of targeted protein degradation to traditionally 'undruggable' targets," said Mathai Mammen, M.D., Ph.D., Chairman and CEO of Parabilis Medicines. "These first compelling data from our ERG program validate our novel approach to degradation. The data also support the continued progress of our ERG degrader toward clinical trials, where it has the potential to be a meaningful therapeutic for patients with metastatic prostate cancer."
Overcoming the "Undruggable" Challenge
ERG has long been recognized as a high-value target in prostate cancer, particularly in metastatic castrate-resistant prostate cancer (mCRPC) where the TMPRSS2-ERG gene fusion is associated with more aggressive disease and may predict resistance to certain therapies, such as PARP inhibitors. Despite its clinical relevance, ERG has remained "undruggable" by conventional inhibitors or first-generation degraders because the protein lacks small molecule binding pockets.
Parabilis's approach leverages the company's proprietary Helicon peptide technology, which enables intracellular targeting of "flat" protein surfaces. The ERG degrader uses Helicon technology to bind directly to the ERG protein and, through its attached E3 ligand, directs the ERG protein to the ubiquitin-proteasome pathway for degradation.
Key Preclinical Findings
The data presented at AACR revealed several significant findings:
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In mice implanted with prostate cancer cell-derived xenograft (CDX) tumors, administration of the ERG degrader produced >90% tumor ERG degradation through 7 days post dose. This corresponded to suppression of ERG's downstream effects on target gene ARHGDIB.
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In both patient- and cell-line derived xenograft (PDX and CDX) models of TMPRSS2-ERG fusion prostate cancer, the ERG degrader significantly inhibited tumor growth.
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RNA sequencing expression analyses indicated that the ERG degrader downregulated Myc target genes.
The company's first-in-class program is currently in late lead optimization, with plans to enter IND-enabling toxicology studies in 2025.
Comprehensive Approach to Prostate Cancer
Parabilis's prostate cancer franchise extends beyond the ERG degrader to include a selective degrader of androgen receptor (AR). This complementary program targets a site outside the canonical androgen-binding site on the protein, potentially addressing a common resistance mechanism that arises in response to AR antagonist therapies.
Together, these degraders could provide novel therapeutic approaches for patients with mCRPC, a disease with significant unmet medical need. The TMPRSS2-ERG gene fusion is particularly relevant in this patient population, where it is associated with more aggressive disease progression.
About Parabilis Medicines
Formerly known as Fog Pharmaceuticals, Parabilis Medicines is a clinical-stage biopharmaceutical company focused on creating cancer therapeutics. The company's Helicon discovery platform engineers stabilized helical peptide therapeutics that can target traditionally undruggable proteins.
The company is advancing a pipeline of first-in-class programs across three domains: functional inhibitors of intracellular protein-protein interactions, targeted protein degraders, and targeted radiopharmaceuticals. Their lead program, FOG-001, is a clinical-stage β-catenin/TCF4 inhibitor.
Headquartered in Cambridge, Massachusetts, Parabilis is well-capitalized, having raised more than $500 million to date from leading life sciences investors.
