Accent Therapeutics announced new preclinical data on its two lead cancer therapy programs at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston. The clinical-stage biopharmaceutical company presented findings on ATX-295, a novel KIF18A inhibitor, and ATX-559, a first-in-class DHX9 inhibitor, both designed to exploit genomic instability in cancer cells for selective tumor destruction.
Targeting Chromosomal Instability with ATX-295
ATX-295 demonstrated enriched activity in preclinical models of ovarian cancer and triple-negative breast cancer (TNBC) that exhibit whole genome doubling (WGD). The compound targets KIF18A, a mitotic kinesin motor protein essential for cell division in tumors with chromosomal instability.
According to the company's data, ATX-295 induced dose-dependent tumor regression in WGD-positive preclinical models, validating whole genome doubling as a strong predictive biomarker for treatment response. The therapy selectively targets aneuploid tumors—those with abnormal chromosome numbers—while leaving healthy cells with normal chromosome counts unaffected.
"Treatment with a KIF18A inhibitor leads to rapid cell death in these chromosomally unstable cancer cells while leaving healthy cells with normal numbers of chromosomes unaffected," the company stated. ATX-295 is currently being evaluated in a Phase 1/2 clinical trial (NCT06799065).
DHX9 Inhibition Addresses Replication Stress
The first-in-class oral DHX9 inhibitor ATX-559 showed potent activity against cancers characterized by high levels of replication stress. Preclinical data demonstrated that ATX-559 increases replicative stress and DNA damage, leading to selective cell death in cancers with genomic instability.
The compound achieved robust, dose-dependent tumor regression in preclinical models with BRCA alterations and microsatellite instability-high (MSI-H) status. DHX9, a DNA/RNA helicase, plays a critical role in tumors with replication stress, including BRCA loss-of-function cancers (breast and ovarian), mismatch repair deficient (dMMR) or MSI-H cancers (colorectal, endometrial, gastric), and other tumor types.
ATX-559 is currently being evaluated in a Phase 1/2 clinical trial (NCT06625515), targeting what the company describes as "large patient populations with significant unmet medical need."
Biomarker-Driven Precision Medicine Strategy
Dr. Serena Silver, Chief Scientific Officer of Accent Therapeutics, emphasized the company's biomarker-driven approach during the conference presentation. "The data presented for our KIF18A and DHX9 programs continue to validate the success of our biomarker-driven strategy against challenging, genetically diverse cancers," Silver said. "By precisely targeting the vulnerabilities created by genomic instability, we are excited about the potential of ATX-295 and ATX-559 to address significant unmet needs for patients."
Silver's presentation, entitled "Addressing Novel Oncology Targets for Tumors with Genomic Instability," highlighted how both therapies exploit genomic instability to achieve cancer-selective growth inhibition in vitro and in vivo. The approach specifically targets cancers with high levels of chromosomal instability, such as ovarian and triple-negative breast cancer for ATX-295, and multiple tumor types with replication stress for ATX-559.
Clinical Development and Market Position
Both programs represent Accent Therapeutics' focus on prosecuting novel tumor vulnerabilities in cancers with high genomic and chromosomal instability. The company retains full worldwide rights to both the KIF18A program, including ATX-295, and the DHX9 program, including ATX-559.
The therapeutic approach addresses what the company identifies as "suboptimally addressed, high-impact oncology targets" with potential benefits for large patient populations. By targeting the maintenance of genomic stability and exploiting vulnerabilities in replication and transcription processes, both compounds aim to achieve cancer-specific cell death while sparing normal tissue.
