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DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor
Philip A Harris, Bryan W King, Deepak Bandyopadhyay
1Platform Technology & Science, GlaxoSmithKline , Winter Street, Waltham, Massachusetts 02451, United States.
Journal of Medicinal Chemistry
|February 9, 2016
Summary
Researchers identified a novel benzoxazepinone inhibitor targeting RIPK1 (receptor interacting protein 1 kinase), crucial in inflammation. This potent and selective inhibitor shows promise for developing new treatments for inflammatory diseases.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Receptor interacting protein 1 (RIPK1) kinase is implicated in tumor necrosis factor (TNF)-mediated inflammation.
- RIPK1 is a promising therapeutic target for inflammatory diseases.
Purpose of the Study:
- To identify novel small-molecule inhibitors of RIPK1 kinase.
- To characterize the selectivity and developability of identified inhibitors.
Main Methods:
- Screening of GSK's DNA-encoded small-molecule libraries against RIPK1.
- Biochemical assays to determine kinase selectivity and species selectivity.
- X-ray crystallography to elucidate inhibitor-bound RIPK1 conformation.
- Site-directed mutagenesis of murine RIPK1.
Main Results:
- Identification of a novel benzoxazepinone inhibitor series with high potency against RIPK1.
- Demonstration of complete monokinase selectivity for RIPK1 and species selectivity (primate vs. nonprimate).
- Elucidation of the binding conformation responsible for selectivity and successful engineering of murine RIPK1 potency.
- Compound 14 (GSK'481) exhibits favorable pharmacokinetics and developability.
Conclusions:
- The benzoxazepinone scaffold represents a promising starting point for developing RIPK1 inhibitors.
- GSK'481 demonstrates a favorable profile for further optimization into a clinical candidate for inflammatory diseases.
