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Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity. | LitMetric

AI Article Synopsis

  • Researchers are exploring the use of bifunctional small molecules to selectively degrade proteins, which could change treatment methods for various diseases.
  • Despite their potential effectiveness, these chimeric molecules face challenges like low solubility and poor pharmacokinetics that make them hard to use in living organisms.
  • A breakthrough was made with a new degrader-antibody conjugate that improved the drug's effectiveness in the body, leading to successful tumor regression in tests.

Article Abstract

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.

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Source
http://dx.doi.org/10.1002/cmdc.201900497DOI Listing

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