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).