ATX968 / Accent Therap - LARVOL DELTA

ATX-559, a first in class DHX9 inhibitor, and targeted therapeutic for molecularly defined tumors with genomic instability and replicative stress (AACR 2025) - P1 | "We previously demonstrated that DHX9 genetic loss or inhibition by the DHX9 tool compound ATX968 was efficacious in tumor types that exhibit DDRD and/or genomic instability; these include tumors with defective mismatch repair and/or high microsatellite instability (dMMR/MSI-H) or alterations in the DDR genes BRCA1 and/or BRCA2 (BRCA).Here we describe ATX-559, a potent, selective, orally bioavailable, small-molecule inhibitor of DHX9 helicase activity that is currently in clinical development. Oral treatment of 45 mg/kg BID demonstrated enriched sensitivity in BRCA altered TNBC (75%) and dMMR/MSI-H (68%) PDX models.Together, these findings represent preclinical pharmacological validation of DHX9 as a selective therapeutic target in cancers that exhibit genomic instability and replication stress. ATX-559 is currently in a first-in-human, Phase 1, open-label, dose-escalation and expansion study in patients with locally advanced or metastatic solid tumors and..."

Breast Cancer • Endometrial Cancer • Gastric Cancer • Microsatellite Instability • Oncology • Oral Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • DHX9 • MSI

Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9. (PubMed, J Med Chem) - "Analysis shows that cell potency more closely correlates with residence time than with equilibrium measurements of binding affinity or biochemical potency. Further optimization of potency and ADME properties led to the identification of ATX968, a potent and selective DHX9 inhibitor that is efficacious in a tumor xenograft model of microsatellite instability-high (MSI-H) colorectal cancer."

Journal • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI

Targeting DHX9 helicase with the novel small-molecule inhibitor ATX968 induces replication stress and innate immunity in small cell lung cancer (AACR 2025) - "Notably, oral treatment with ATX968 monotherapy resulted in robust and durable tumor regression in SCLC mouse xenograft models, which was tolerable over a 28-day treatment period. Together, these findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, and inhibitors of DHX9 represent a promising new therapeutic strategy for SCLC treatment and potentially other "cold" tumors characterized by replication stress and genomic instability."

Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair. (PubMed, Cancer Res) - "ATX968 was identified as a potent and selective inhibitor of DHX9 helicase activity...These preclinical data validate DHX9 as a target for the treatment of patients with MSI-H/dMMR. Additionally, this potent and selective inhibitor of DHX9 provides a valuable tool with which to further explore the effects of inhibition of DHX9 enzymatic activity on the proliferation of cancer cells in vitro and in vivo."

Journal • Mismatch repair • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • DHX9 • MSI

DHX9 inhibition as a novel therapeutic for cancer with loss-of-function mutations in DNA damage repair genes BRCA1 and BRCA2 (AACR 2024) - "DHX9 small molecule inhibitor ATX968 was tested for anti-proliferative activity in a large cell panel of 300 cell lines, and bioinformatic analyses was performed to identify molecular variants that co-associate with sensitivity or resistance cell proliferation outcomes...These results extend the opportunity for DHX9 inhibition to provide therapeutic benefit for patients with solid tumors beyond what was previously reported for MSI-H CRC. Together, this preclinical data package validates DHX9 as a tractable new target with potential utility as a novel treatment for patients with defective DNA repair, such as MMR and BRCA1 and/or BRCA2 LOF, across multiple tumor types including colorectal, breast and ovarian cancer."

Breast Cancer • Microsatellite Instability • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • MSI • WRN

Accent Therapeutics Presents Data Supporting Two Lead Programs at AACR 2024 Annual Meeting (PRNewswire) - "Data describing a DHX9-specific pharmacodynamic biomarker of inhibition are presented in a poster entitled 'circBRIP1 RNA as a non-invasive target engagement pharmacodynamic biomarker for DHX9 inhibition.' Key takeaways include: Positive correlation of circBRIP1 induction with DHX9 biochemical activity, dose, and exposure for DHX9 inhibitors. Similar potency of dose-dependent induction of circBRIP1 across cell lines that are sensitive or insensitive to DHX9 inhibition, indicating that circBRIP1 is a unique target engagement PD biomarker, but not a predictor of DHX9 sensitivity. circBRIP1 induction correlates with DHX9 inhibitor concentration within individual tumors in mouse xenografts, providing strong evidence of a predictable PK/PD relationship."

Biomarker • Preclinical • Oncology

Accent Therapeutics Presents Data Supporting Two Lead Programs at AACR 2024 Annual Meeting (PRNewswire) - "Accent Therapeutics...presents advances in cancer targeting, including data on DHX9...inhibitor activity in multiple tumor types, at the 2024 American Association for Cancer Research (AACR) Annual Meeting....DHX9 inhibition results in DNA damage and catastrophic increase in replication stress in BRCA LOF cell lines, causing cell cycle arrest prior to onset of apoptosis. In vivo, DHX9 inhibitors were well tolerated and demonstrate robust tumor growth inhibition in multiple BRCA LOF cell line xenograft models."

Preclinical • Breast Cancer

Accent Therapeutics Sees Promise in Therapies Targeting RNA-Modifying Proteins (Precision Medicine Online) - "Accent Therapeutics is advancing the first of its pipeline drugs targeting RNA-modifying proteins into investigational new drug (IND)-enabling studies in a range of cancers including tumors with microsatellite instability...Accent has selected a lead drug candidate and begun investigational new drug application-enabling studies with the intention of submitting an application in the second half of 2024, which if cleared by the FDA will allow it to take the agent into clinical trials...In preclinical studies, targeting DHX9 was lethal to cancer cells, and in mice, reduction of DHX9 expression did not have any adverse effects on body weight, blood biochemistry, and histology of various tissues compared to control mice...inhibitors of DHX9 had anti-proliferative activity in MSI colorectal cancer cells with defective mismatch repair and that oral dosing of mice with the DHX9 inhibitor ATX968 resulted in robust and durable tumor regression correlating with intra-tumoral..."

IND • New molecule • Preclinical • Colorectal Cancer • Microsatellite Instability

DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer. (AACR-NCI-EORTC 2023) - No abstract available

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Accent Therapeutics Unveils XRN1 Program and Provides Pipeline Update with Presentations at 35th AACR-NCI-EORTC Symposium (PRNewswire) - "ADAR1 has emerged as a promising, yet challenging-to-drug, oncology target for which inhibition has been shown to induce downstream immune activation and subsequent cell death in cancer cells with high intrinsic type 1 interferon signaling-a trait that 15-30% of primary tumors share....The company's final presentation at the meeting...will demonstrate that DHX9 inhibition in microsatellite instable tumors exhibiting defective mismatch repair induces replication stress and subsequent cell death."

Preclinical • Solid Tumor