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

被引:108
作者
Dragovich, Peter S. [1 ]
Pillow, Thomas H. [1 ]
Blake, Robert A. [1 ]
Sadowsky, Jack D. [1 ]
Adaligil, Emel [1 ]
Adhikari, Pragya [1 ]
Bhakta, Sunil [1 ]
Blaquiere, Nicole [1 ]
Chen, Jinhua [2 ]
Dela Cruz-Chuh, Josefa [1 ]
Gascoigne, Karen E. [1 ]
Hartman, Steven J. [1 ]
He, Mingtao [3 ]
Kaufman, Susan [1 ]
Kleinheinz, Tracy [1 ]
Kozak, Katherine R. [1 ]
Liu, Liang [3 ]
Liu, Liling [1 ]
Liu, Qi [3 ]
Lu, Ying [2 ]
Meng, Fanwei [3 ]
Mulvihill, Melinda M. [1 ]
O'Donohue, Aimee [1 ]
Rowntree, Rebecca K. [1 ]
Staben, Leanna R. [1 ]
Staben, Steven T. [1 ]
Wai, John [2 ]
Wang, Jian [2 ]
Wei, BinQing [1 ]
Wilson, Catherine [1 ]
Xin, Jianfeng [3 ]
Xu, Zijin [2 ]
Yao, Hui [2 ]
Zhang, Donglu [1 ]
Zhang, Hongyan [2 ]
Zhou, Hao [2 ]
Zhu, Xiaoyu [2 ]
机构
[1] Genentech Inc, San Francisco, CA 94080 USA
[2] WuXi AppTec, Shanghai 200131, Peoples R China
[3] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China
关键词
D O I
10.1021/acs.jmedchem.0c01845
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 antigendependent 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 antigendependent antiproliferation effects in LNCaP prostate cancer cells.
引用
收藏
页码:2534 / 2575
页数:42
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