Optimization of HJB97 for The Design of PROTAC Degraders of BET Proteins
Posted On 2019-04-01
The Bromodomain and Extra-Terminal Domain (BET) family of proteins comprises BRD2, BRD3, BRD4, and BRDT. The BET proteins are epigenetic readers and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer.
The targeted degradation of BET proteins using PROTAC technology causes cell death and results in tumor growth inhibition. BET targeting PROTACs show pronounced and long-lasting anti-proliferative effect. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules, which recruit a target protein to an E3 ubiquitin ligase to trigger protein degradation.
A recent study designed heterobifunctional BET degraders to induce BET protein degradation. These molecules contain a ligand for a target protein connected via a linker to a ligand for an E3 ubiquitin ligase. One of the most promising compounds, BETd-260, effectively degrades BRD4 protein at concentrations as low as 30 pM.
They performed the further optimization for these of BET inhibitors. They identified HJB97 as a high-affinity BET inhibitor. Addition of the BET inhibitor HJB97 effectively blocks the degradation of BRD2, BRD3, and BRD4 proteins induced by BETd-260. HJB97 binds to BRD2, BRD3, and BRD4 with high affinities and is >10 times more potent than (+)-JQ-1 or Birabresib (OTX-015) in FP-based competitive binding assays.
In view of the above-mentioned facts, BET inhibitors have therapeutic potential for the treatment of human cancers.
Zhou B, et al. Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression. J Med Chem. 2018 Jan 25;61(2):462-481.