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

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

  • J Med Chem. 2021 Mar 11;64(5):2534-2575. doi: 10.1021/acs.jmedchem.0c01845.
Peter S Dragovich 1,  Thomas H Pillow 1,  Robert A Blake 1,  Jack D Sadowsky 1,  Emel Adaligil 1,  Pragya Adhikari 1,  Sunil Bhakta 1,  Nicole Blaquiere 1,  Jinhua Chen 2,  Josefa Dela Cruz-Chuh 1,  Karen E Gascoigne 1,  Steven J Hartman 1,  Mingtao He 3,  Susan Kaufman 1,  Tracy Kleinheinz 1,  Katherine R Kozak 1,  Liang Liu 3,  Liling Liu 1,  Qi Liu 3,  Ying Lu 2,  Fanwei Meng 3,  Melinda M Mulvihill 1,  Aimee O'Donohue 1,  Rebecca K Rowntree 1,  Leanna R Staben 1,  Steven T Staben 1,  John Wai 2,  Jian Wang 2,  BinQing Wei 1,  Catherine Wilson 1,  Jianfeng Xin 3,  Zijin Xu 2,  Hui Yao 2,  Donglu Zhang 1,  Hongyan Zhang 2,  Hao Zhou 2,  Xiaoyu Zhu 2
Affiliations

Affiliations

  • 1 Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, China.
PMID: 33596065 DOI: 10.1021/acs.jmedchem.0c01845
Abstract

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.

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