Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity

Abstract

Starting from a nonselective bromodomain and extraterminal (BET) inhibitor and a cereblon ligand, we have used precise conformational control for the development of two potent and highly selective BRD4 degraders, BD-7148 and BD-9136. These compounds induce rapid degradation of BRD4 protein in cells at concentrations as low as 1 nM and demonstrate ≥1000-fold degradation selectivity over BRD2 or BRD3 protein. Proteomic analysis of >5700 proteins confirmed their highly selective BRD4 degradation. A single dose of BD-9136 selectively and effectively depletes BRD4 protein in tumor tissues for >48 h. BD-9136 effectively inhibits tumor growth without adverse effects on mice and is more efficacious than the corresponding pan BET inhibitor. This study suggests selective degradation of BRD4 as a strategy for the treatment of human cancers and demonstrates a strategy for the design of highly selective PROTAC degraders.

Degraders in epigenetic therapy: PROTACs and beyond

“…Furthermore, it was found to be isoform-selective, as it did not induce degradation of BRD2/3 at concentrations > 10 μM. Wang et al created a new BRD4 PROTAC, BD-764 (compound 6) (Figure 4A), through the conjugation of QCA276, a pan BET inhibitor previously described, with pomalidomide, a CRBN ligand, using a flexible ethylamino linker [28]. Through precise manipulation of the linker, BD-764, a potent and extremely specific BRD4 degrader, led to the acquisition of BD-7148 (compound 7) (Figure 4A) and its more soluble analog, BD-9136 (compound 8) (Figure 4A).…”

Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders

“…The general synthesis route is briefly outlined in Scheme 1. We began with commercially available 5-bromo-2-naphthoic acid (29) We first evaluated the antiproliferative activities of our synthesized compounds in NF2-deficient NCI-H226 cells, with the results outlined in Table 1. Compounds 16−22, which bear alkyl linkers of varying lengths, displayed comparable antiproliferative activities, with potency around 1 μM.…”

“…Furthermore, the development of isoform-selective inhibitors could be a significant challenge owing to the high structural similarity among traditional inhibitor binding sites across various isoforms. Nevertheless, a range of PROTACs derived from pan-inhibitors have successfully achieved isoform-selective degradation. − This may be attributed to the fact that PROTAC requires the formation of a POI–PROTAC–E3 ternary complex to induce protein degradation. Each isoform can potentially form distinct ternary complexes, which differ in their capacities of inducing protein degradation. ,, …”

Paralogue-selective degradation of the lysine acetyltransferase EP300

“…In addition to the well-characterized HAT 10 and BRD [32][33][34] ligands, there are now multiple potent dual degraders based on BRD ligands. [13][14][15][16]35 JQAD-1 and MC-1 add to this collection by affording paralogue-specific degradation and -in the case of MC-1, and possibly JQAD-1 as well -dual HAT inhibition at high concentrations. In this latter scenario, MC-1 may be deployed as an augmented HAT inhibitor with an additional capability to degrade EP300.…”