2. Academic Validation
  3. Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy

  • J Med Chem. 2021 Mar 11;64(5):2576-2607. doi: 10.1021/acs.jmedchem.0c01846.
Peter S Dragovich 1,  Thomas H Pillow 1,  Robert A Blake 1,  Jack D Sadowsky 1,  Emel Adaligil 1,  Pragya Adhikari 1,  Jinhua Chen 2,  Nicholas Corr 1,  Josefa Dela Cruz-Chuh 1,  Geoffrey Del Rosario 1,  Aaron Fullerton 1,  Steven J Hartman 1,  Fan Jiang 3,  Susan Kaufman 1,  Tracy Kleinheinz 1,  Katherine R Kozak 1,  Liling Liu 1,  Ying Lu 2,  Melinda M Mulvihill 1,  Jeremy M Murray 1,  Aimee O'Donohue 1,  Rebecca K Rowntree 1,  William S Sawyer 1,  Leanna R Staben 1,  John Wai 2,  Jian Wang 2,  BinQing Wei 1,  Wentao Wei 3,  Zijin Xu 2,  Hui Yao 2,  Shang-Fan Yu 1,  Donglu Zhang 1,  Hongyan Zhang 2,  Shenhua Zhang 3,  Yongxin Zhao 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 Viva Biotech, Structural Biology, 334 Aidisheng Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
PMID: 33596073 DOI: 10.1021/acs.jmedchem.0c01846
Abstract

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform the field of medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) in the chemical literature, enable the controlled degradation of specific proteins via their direction to the cellular Proteasome. In this report, we describe the second phase of our research focused on exploring antibody-drug conjugates (ADCs), which incorporate BRD4-targeting chimeric degrader entities. We employ a new BRD4-binding fragment in the construction of the chimeric ADC payloads that is significantly more potent than the corresponding entity utilized in our initial studies. The resulting BRD4-degrader antibody conjugates exhibit potent and antigen-dependent BRD4 degradation and antiproliferation activities in cell-based experiments. Multiple ADCs bearing chimeric BRD4-degrader payloads also exhibit strong, antigen-dependent antitumor efficacy in mouse xenograft assessments that employ several different tumor models.

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