On October 10, 2023 Accent Therapeutics, a biopharmaceutical company pioneering a new class of small molecule precision cancer therapies, reported that it will present data unveiling a novel, previously undisclosed program in two poster presentations at the 35th AACR (Free AACR Whitepaper)-NCI-EORTC Symposium held October 11-15, 2023 in Boston, Massachusetts (Press release, Accent Therapeutics, OCT 10, 2023, View Source [SID1234635825]). The company will also present data supporting development of its ADAR1 and DHX9 programs in two additional poster presentations.
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5′→3′ exoribonuclease 1 (XRN1) is an enzyme that degrades single- and double-stranded RNA, playing roles in extracellular mRNA turnover and innate immunity through prevention of dsRNA accumulation and subsequent MDA5 and PKR-mediated immune signaling. Accent has identified XRN1 as a key vulnerability for therapeutic targeting of tumors with elevated type I interferon signaling and is developing small molecule inhibitors of this compelling oncology target, for which there are none currently disclosed.
Two of the company’s presentations at the meeting describe the preclinical validation of XRN1 as an oncology target and the subsequent characterization of selective inhibitors of XRN1. XRN1 knockout resulted in cell death due to accumulation of dsRNA and downstream activation of the MDA5 and PKR innate immune pathways in cells with intrinsically elevated type I interferon signaling, but not in those with low interferon signaling. Accent has identified novel, potent, and selective allosteric inhibitors that bind XRN1 with nanomolar target affinity without binding to XRN2.
"We are excited to share our progress advancing our portfolio and to introduce our XRN1 inhibitor program as a potentially impactful approach to helping cancer patients," said Robert Copeland, Ph.D., President and Chief Scientific Officer of Accent Therapeutics. "These data demonstrate the versatility and promise of pursuing critical intracellular dependences of cancer biology to identify novel oncology targets with the potential to benefit broad patient populations."
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. Accent will also present its innovative suite of in vitro and cellular assays that enable identification of small molecule inhibitors of ADAR1. The resulting compounds are shown to potently inhibit cell growth in a cancer cell line with high interferon type 1 signaling.
The company’s final presentation at the meeting will highlight its progress developing small molecule inhibitors of the novel oncology target DHX9, an RNA helicase that has been reported to play important roles in the maintenance of genomic stability in multiple cancer types. The presentation will demonstrate that DHX9 inhibition in microsatellite instable tumors exhibiting defective mismatch repair induces replication stress and subsequent cell death.
The poster presentations will be archived on the Accent website following the meeting.
Details for the presentations are as follows:
Title: Exoribonuclease XRN1 is a Therapeutic Vulnerability in Tumors with Intrinsically Elevated Type I Interferon Signaling
Abstract Number: A163
Session & Location: Poster Session A – Exhibit Hall D
Session Date & Time: Thursday, October 12, 12:30 pm – 4:00 pm ET
Presenter: Maureen M. Lynes, Ph.D.
Title: Discovery of Small Molecule Inhibitors of ADAR1
Abstract Number: A170
Session & Location: Poster Session A – Exhibit Hall D
Session Date & Time: Thursday, October 12, 12:30 pm – 4:00 pm ET
Presenter: Shane M. Buker, Ph.D.
Title: Characterization of Selective, Allosteric Inhibitors of Human XRN1
Abstract Number: B073
Session & Location: Poster Session B – Exhibit Hall D
Session Date & Time: Friday, October 13, 12:30 pm – 4:00 pm ET
Presenter: Gordon J. Lockbaum, Ph.D.
Title: DHX9 Inhibition as a Novel Therapeutic Modality in Microsatellite Instable Colorectal Cancer
Abstract Number: C087
Session & Location: Poster Session C – Exhibit Hall D
Session Date & Time: Saturday, October 14, 12:30 pm – 4:00 pm ET
Presenter: Jennifer Castro
About XRN1
XRN1 is an RNA exonuclease that plays important roles in innate immunity by preventing double-stranded RNA (dsRNA) accumulation. Tumors with intrinsic type I interferon signaling are acutely sensitive to XRN1 loss, making it a strong oncology target. Inhibitors of XRN1 have potential for use as monotherapy and in combination with immuno-oncology therapeutics. Accent is applying structure-based design approaches to develop potent and selective small molecule inhibitors of XRN1 to address cancer indications with high unmet medical need.
About ADAR1
Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme that edits double-stranded RNA (dsRNA) to prevent recognition and downstream immune signaling. In tumor cells with high interferon signaling, small molecule inhibitors of ADAR1 have been shown to induce selective cell killing and immune sensitization, making it a highly attractive target for monotherapy and combination approaches with immunotherapies, such as checkpoint inhibitors. Accent is developing ADAR1 targeted therapies to address many solid tumor indications with significant unmet need, including non-small cell lung cancer, triple-negative breast cancer, ovarian cancer, and head and neck squamous cell carcinomas.
About DHX9
Accent’s lead program is a first-in-class DHX9 inhibitor with the potential to address high unmet need indications that lack targeted therapies; these include colorectal, endometrial, gastric, and other high microsatellite instable (MSI-H) cancers. Several additional undisclosed cancer types representing large patient populations are also being explored based on their sensitivities to DHX9 inhibition. DHX9 is a DNA/RNA helicase that has been reported to play important roles in replication, transcription, translation, RNA splicing, RNA processing, and maintenance of genomic stability. Hence, this enzyme represents a compelling novel oncology target as inhibition of DHX9 exploits key tumor vulnerabilities, resulting in cancer-specific death. Accent is currently conducting IND-enabling studies evaluating its DHX9 inhibitor.