Structure–activity relationships in a series of dihydrouracil–JQ1 conjugates: discovery of highly potent BRD4 degraders

A detailed study of structure-activity relationship (SAR) in a series of phenyl dihydrouracil (PHDU) derivatives as promising chemotypes for protein degrader discovery is reported. Evaluation of cereblon binding for several dozen PHDU-derived building blocks showed that over 20 compounds with various substituents at the phenyl ring showed over 50% displacement of labeled Thalidomide at 10 M. Most potent representatives bearing methyl substituent were used to synthesize 72 PROTACs by conjugating with JQ-1 though a series of linear linkers with or without additional heteroatoms. A series of assays (including binary and ternary complex formation, as well as cell-based BRD4 degradation) allowed establishing SAR trends regarding the linker nature and length. Compounds with (CH₂)₅, (CH₂)₆, and especially (CH₂)₁₁ linkers demonstrated the best results in both BRD4 degradation (DC₅₀ = 16–52 nM) and cell viability assays. The most potent representatives (2/5-Me-PDHU11) can be promising tools for biomedical research.