BRD4 is a member of the bromodomain and extra-terminal (BET) family of proteins (BRD2, 3, 4 and T) and functions as an epigenetic “reader” of acetylated histone lysine residues via its two bromodomain motifs (BRD1 and BRD2). Disruption of BRD4-histone interactions is currently viewed as an attractive strategy for the development of novel anti-cancer agents, and many BRD4 inhibitors are currently undergoing clinical trials for various oncology indications. Recently, chimeric Chemical Inducers of DEgradation (CIDEs) which form ternary complexes between BRD4 and various E3 ligases (e.g., VHL, CRBN, XIAP, MDM2) were shown to potently degrade the BRD4 protein, and these entities may offer additional therapeutic opportunities relative to simple inhibitors. As part of our exploration of BRD4-targeting CIDE molecules, we unexpectedly discovered a monomeric (i.e., non-chimeric) small molecule which potently degraded the BRD4 protein in a manner that was similar to that observed for larger CIDE compounds. This presentation describes the identification of this novel, small-molecule BRD4 degrader (GNE-0011) along with its chemical, structural, and biological characterization. GNE-0011 was highly active in cell-based assessments of MYC transcription inhibition activity and antiproliferation properties. It also exhibited stronger potency in these in vitro assays as compared to structurally-related BRD4 inhibitors which did not degrade the protein. In addition, western blot and global proteomics analyses indicated relatively selective GNE-0011-mediated degradation of BRD4 over the closely related BRD3 and BRD2 BET family members. GNE-0011 was active in a mouse xenograft tumor model in vivo where it also exhibited significant intratumor degradation of the BRD4 protein. Several GNE-0011 analogs were subsequently synthesized (both active and inactive molecules), and the resulting structure-activity relationships will be disclosed. A crystal structure of GNE-0011 in complex with BRD4 will also be presented and discussed.

Discovery and characterization of a novel small molecule BRD4 protein degrader

2019 Fall National Meeting

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