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

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., dua...

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Bibliographic Details
Published in:ChemMedChem 2020-09, Vol.15 (18), p.1752-1756
Main Authors: Catalano, Marco, Moroglu, Mustafa, Balbi, Petra, Mazzieri, Federica, Clayton, James, Andrews, Katrina H., Bigatti, Martina, Scheuermann, Jörg, Conway, Stuart J., Neri, Dario
Format: Article
Language:English
Subjects:
Affinity
AMP
Assembly
Bar codes
Complementary DNA
CREBBP bromodomain
DNA-encoded chemical library
encoded self-assembly chemical library
inhibitors
medicinal chemistry
Cyclic AMP response element-binding protein
Deoxyribonucleic acid
DNA
Enzyme-linked immunosorbent assay
Extremities
Fluorescence
Fluorescence polarization
Fragments
Gene sequencing
Libraries
Lysine
Pharmacology
Proteins
Selectivity
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Summary: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). Screening against the CREB‐binding protein (CREBBP) bromodomain of a dual‐pharmacophore encoded self‐assembly chemical (ESAC) library led to the discovery of a novel synergistic pair of binding fragments, presenting sub‐micromolar affinity for CREBBP.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000528