Histone

Gene

Network packet

Cell biology

Conjugate

Biotechnology

Biology

Prostate cancer

Epigenetics

Operating system

Bromodomain

Cancer research

Biochemistry

Computer science

LNCaP

Linker

Computational biology

Computer network

Immunology

Genetics

Bioorthogonal chemistry

In vivo

Combinatorial chemistry

Monoclonal antibody

Payload (computing)

Mathematics

Click chemistry

Mathematical analysis

BRD4

Chemistry

Epitope

Antibody

Cancer

Journal of Medicinal Chemistry

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) and related chimeric molecules that effect intracellular degradation of target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these chimeric entities are relatively large compounds that often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation of such molecules to monoclonal antibodies using technologies originally developed for cytotoxic payloads so as to provide alternate delivery options for these novel agents. In this report, we describe the first phase of our systematic development of antibody–drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting chimeric degrader entities. We demonstrate the antigen-dependent delivery of the degrader payloads to PC3-S1 prostate cancer cells along with related impacts on MYC transcription and intracellular BRD4 levels. These experiments culminate with the identification of one degrader conjugate, which exhibits antigen-dependent antiproliferation effects in LNCaP prostate cancer cells.

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties