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Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9
Matthew H Daniels1, Jennifer Castro1, Young-Tae Lee1
1Accent Therapeutics, Inc., 1050 Waltham Street, Lexington, Massachusetts 02421, United States.
Abstract:
DHX9 is an RNA/DNA helicase integral in the maintenance of genome stability that has emerged as an attractive target for oncology drug discovery. Disclosed herein is the discovery and optimization of a series of DHX9 inhibitors. Compound 1 was identified as a partial inhibitor of DHX9 ATPase activity but a full inhibitor of unwinding activity. Binding of 1 to a pocket distinct from the ATP binding site was confirmed by X-ray crystallography, enabling structure-based drug optimization. During this optimization, a sulfur-halogen bond was identified that increased on-target residence time without impacting equilibrium binding affinity. 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.
Insights
Researchers discovered new DHX9 inhibitors for cancer therapy. ATX968, a potent DHX9 inhibitor, showed efficacy in microsatellite instability-high colorectal cancer models, highlighting the importance of residence time for drug potency.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- DHX9 (DEAH-box helicase 9) is crucial for maintaining genome stability.
- DHX9 is a promising therapeutic target for cancer drug discovery.
Purpose of the Study:
- To discover and optimize novel DHX9 inhibitors.
- To investigate the relationship between binding kinetics and cellular potency.
Main Methods:
- Structure-based drug design utilizing X-ray crystallography.
- Biochemical assays measuring ATPase and unwinding activity.
- In vivo efficacy studies in tumor xenograft models.
Main Results:
- Compound 1 demonstrated selective inhibition of DHX9 unwinding activity.
- A sulfur-halogen bond enhanced on-target residence time.
- Cell potency correlated better with residence time than equilibrium binding affinity.
- ATX968, a potent DHX9 inhibitor, showed efficacy in MSI-H colorectal cancer models.
Conclusions:
- DHX9 inhibitors represent a viable therapeutic strategy for oncology.
- Optimizing residence time is critical for developing potent DHX9 inhibitors.
- ATX968 is a promising candidate for treating MSI-H colorectal cancer.
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