Identification of triazolyl KAT6 inhibitors via a templated fragment approach
Chun Chen1, Sarah B Pawley1, Joy M Cote1
1Prelude Therapeutics Incorporated, 175 Innovation Boulevard, Wilmington, DE 19805, USA.
Abstract:
KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER+ breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date. Here, we report the fragment-based discovery of a series of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide KAT6 inhibitors and early hit-to-lead efforts to improve the KAT6 potency.
Insights
Researchers discovered novel KAT6 inhibitors for cancer therapy. These compounds target the KAT6A gene, implicated in poor outcomes for ER-positive breast cancer patients, aiming to improve treatment options.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- KAT6 (MYST family histone acetyltransferase) regulates cell cycle and senescence.
- KAT6A gene amplification correlates with poor prognosis in ER-positive breast cancer.
- No KAT6 inhibitors are currently approved for clinical use.
Purpose of the Study:
- To report the fragment-based discovery of novel KAT6 inhibitors.
- To initiate hit-to-lead optimization for enhanced KAT6 inhibitory potency.
Main Methods:
- Fragment-based drug discovery approach.
- Synthesis of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide derivatives.
- Assays to evaluate KAT6 inhibitory activity and potency.
Main Results:
- Identification of a series of novel KAT6 inhibitors based on the N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide scaffold.
- Demonstration of early-stage hit-to-lead optimization efforts.
Conclusions:
- The identified compounds represent promising starting points for developing new KAT6-targeted cancer therapies.
- Further optimization is warranted to develop potent and clinically viable KAT6 inhibitors.
