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

Autor:	Dragovich PS; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Pillow TH; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Blake RA; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Sadowsky JD; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Adaligil E; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Adhikari P; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Bhakta S; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Blaquiere N; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Chen J; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Dela Cruz-Chuh J; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Gascoigne KE; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Hartman SJ; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., He M; Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, China., Kaufman S; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Kleinheinz T; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Kozak KR; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Liu L; Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, China., Liu L; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Liu Q; Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, China., Lu Y; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Meng F; Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, China., Mulvihill MM; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., O'Donohue A; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Rowntree RK; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Staben LR; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Staben ST; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Wai J; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Wang J; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Wei B; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Wilson C; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Xin J; Pharmaron Beijing, Co. Ltd., 6 Tai He Road, BDA, Beijing 100176, China., Xu Z; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Yao H; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Zhang D; Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States., Zhang H; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Zhou H; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China., Zhu X; WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Mar 11; Vol. 64 (5), pp. 2534-2575. Date of Electronic Publication: 2021 Feb 17.
DOI:	10.1021/acs.jmedchem.0c01845
Abstrakt:	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.
Databáze:	MEDLINE
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