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Design and Synthesis of Biaryl DNA-Encoded Libraries
Yun Ding1, G Joseph Franklin1, Jennifer L DeLorey1
1GlaxoSmithKline , Platform Technology & Science, ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
ACS Combinatorial Science
|August 30, 2016
Summary
DNA-encoded library technology (DELT) enables the discovery of small-molecule ligands. A novel biaryl library identified potent hits for phosphoinositide 3-kinase alpha (PI3Kα).
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- DNA-encoded library technology (DELT) is a powerful method for identifying novel small-molecule ligands.
- Developing diverse and synthetically accessible DNA-encoded libraries is crucial for target-based screening.
Purpose of the Study:
- To design and synthesize novel biaryl DNA-encoded libraries.
- To apply DELT for the discovery of ligands targeting phosphoinositide 3-kinase alpha (PI3Kα).
Main Methods:
- Synthesis of biaryl DNA-encoded libraries utilizing a 5-formyl 3-iodobenzoic acid scaffold.
- Employing three distinct chemical reactions on a DNA template: acylation, Suzuki-Miyaura coupling, and reductive amination.
- Screening a library of 3.5 million compounds against PI3Kα.
Main Results:
- Successfully designed and synthesized a novel biaryl DNA-encoded library.
- The library exhibited a diversity of 3.5 million compounds.
- Potent small-molecule hits targeting PI3Kα were identified from the library.
Conclusions:
- The developed biaryl DNA-encoded library is effective for hit identification.
- DELT, using this scaffold and methodology, is a viable strategy for discovering PI3Kα inhibitors.
- This approach accelerates the identification of novel drug leads.
