2127875-65-2Relevant academic research and scientific papers
Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties
Dragovich, Peter S.,Pillow, Thomas H.,Blake, Robert A.,Sadowsky, Jack D.,Adaligil, Emel,Adhikari, Pragya,Bhakta, Sunil,Blaquiere, Nicole,Chen, Jinhua,Dela Cruz-Chuh, Josefa,Gascoigne, Karen E.,Hartman, Steven J.,He, Mingtao,Kaufman, Susan,Kleinheinz, Tracy,Kozak, Katherine R.,Liu, Liang,Liu, Liling,Liu, Qi,Lu, Ying,Meng, Fanwei,Mulvihill, Melinda M.,O'Donohue, Aimee,Rowntree, Rebecca K.,Staben, Leanna R.,Staben, Steven T.,Wai, John,Wang, Jian,Wei, Binqing,Wilson, Catherine,Xin, Jianfeng,Xu, Zijin,Yao, Hui,Zhang, Donglu,Zhang, Hongyan,Zhou, Hao,Zhu, Xiaoyu
, p. 2534 - 2575 (2021/03/09)
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.
NEODEGRADER CONJUGATES
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Paragraph 0517, (2021/10/11)
The present disclosure provides neoDegraders and neoDegraders conjugated to binding moieties. Also provided are compositions comprising the conjugates. The compounds and compositions are useful for treating a disease or condition, e.g., cancer, in a subject in need thereof.
CYTOTOXIC BIS-BENZODIAZEPINE DERIVATIVES AND CONJUGATES THEREOF WITH CELL-BINDING AGENTS FOR INHIBITING ABNORMAL CELL GROWTH OR FOR TREATING PROLIFERATIVE DISEASES
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Paragraph 00274, (2020/10/20)
The invention relates to benzodiazepine derivatives with antiproliferative activity and more specifically to benzodiazepine compounds of formulae (I), (II), (TI) and (T2). The invention also provides conjugates of the benzodiazepine compounds linked to a
CONJUGATED CHEMICAL INDUCERS OF DEGRADATION AND METHODS OF USE
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Page/Page column 411; 413, (2020/05/28)
The subject matter described herein is directed to antibody-CIDE conjugates (Ab-CIDEs), to pharmaceutical compositions containing them, and to their use in treating diseases and conditions where targeted protein degradation is beneficial.
Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity
Pillow, Thomas H.,Adhikari, Pragya,Blake, Robert A.,Chen, Jinhua,Del Rosario, Geoffrey,Deshmukh, Gauri,Figueroa, Isabel,Gascoigne, Karen E.,Kamath, Amrita V.,Kaufman, Susan,Kleinheinz, Tracy,Kozak, Katherine R.,Latifi, Brandon,Leipold, Douglas D.,Sing Li, Chun,Li, Ruina,Mulvihill, Melinda M.,O'Donohue, Aimee,Rowntree, Rebecca K.,Sadowsky, Jack D.,Wai, John,Wang, Xinxin,Wu, Cong,Xu, Zijin,Yao, Hui,Yu, Shang-Fan,Zhang, Donglu,Zang, Richard,Zhang, Hongyan,Zhou, Hao,Zhu, Xiaoyu,Dragovich, Peter S.
supporting information, p. 17 - 25 (2019/11/20)
The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
