Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity

ChemMedChem. 2020 Jan 7;15(1):17-25. doi: 10.1002/cmdc.201900497. Epub 2019 Nov 14.


The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

Keywords: BRD4; antibodies; antibody-drug conjugate; chimeric protein degrader; drug delivery.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / immunology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Carriers / chemistry
  • Female
  • Half-Life
  • Heterocyclic Compounds, 4 or More Rings / chemistry*
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use
  • Lectins, C-Type / immunology
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, SCID
  • Protein Binding
  • Proteolysis / drug effects
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors, Mitogen / immunology
  • Surface Plasmon Resonance
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • BRD4 protein, human
  • CLEC12A protein, human
  • Cell Cycle Proteins
  • Drug Carriers
  • Heterocyclic Compounds, 4 or More Rings
  • Immunoconjugates
  • Lectins, C-Type
  • Proto-Oncogene Proteins c-myc
  • Receptors, Mitogen
  • Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human