Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library.

ChemMedChem
Marco CatalanoDario Neri

Abstract

DNA-encoded chemical libraries (DECLs) are collections of chemical moieties individually coupled to distinctive DNA barcodes. Compounds can be displayed either at the end of a single DNA strand (i. e., single-pharmacophore libraries) or at the extremities of two complementary DNA strands (i. e., dual-pharmacophore libraries). In this work, we describe the use of a dual-pharmacophore encoded self-assembly chemical (ESAC) library for the affinity maturation of a known 4,5-dihydrobenzodiazepinone ring (THBD) acetyl-lysine (KAc) mimic for the cyclic-AMP response element binding protein (CREB) binding protein (CREBBP or CBP) bromodomain. The new pair of fragments discovered from library selection showed a sub-micromolar affinity for the CREBBP bromodomain in fluorescence polarization and ELISA assays, and selectivity against BRD4(1).

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Citations

Dec 10, 2020·ChemMedChem·Verena B K KunigAndreas Brunschweiger
Dec 5, 2020·Future Medicinal Chemistry·Daniel ConoleMichael J Waring
May 15, 2021·Trends in Chemistry·Shivani PatelGary A Molander

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