19364-66-0Relevant articles and documents
Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
Dragovich, Peter S.,Adhikari, Pragya,Blake, Robert A.,Blaquiere, Nicole,Chen, Jinhua,Cheng, Yun-Xing,den Besten, Willem,Han, Jinping,Hartman, Steven J.,He, Jintang,He, Mingtao,Rei Ingalla, Ellen,Kamath, Amrita V.,Kleinheinz, Tracy,Lai, Tommy,Leipold, Douglas D.,Li, Chun Sing,Liu, Qi,Lu, Jiawei,Lu, Ying,Meng, Fanwei,Meng, Lingyao,Ng, Carl,Peng, Kaishan,Lewis Phillips, Gail,Pillow, Thomas H.,Rowntree, Rebecca K.,Sadowsky, Jack D.,Sampath, Deepak,Staben, Leanna,Staben, Steven T.,Wai, John,Wan, Kunpeng,Wang, Xinxin,Wei, BinQing,Wertz, Ingrid E.,Xin, Jianfeng,Xu, Keyang,Yao, Hui,Zang, Richard,Zhang, Donglu,Zhou, Hao,Zhao, Yongxin
, (2020/01/08)
Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.
Intramolecular End-to-End Reactions of Photoactive Terminal Groups Linked by Poly(oxyethylene) Chains
Ashikaga, Kazuo,Ito, Shinzaburo,Yamamoto, Masahide,Nishijima, Yasunori
, p. 2443 - 2450 (2007/10/02)
The triplet-sensitized photochemical reaction using a series of poly(oxyethylene) chains with a pair of photoactive terminal groups, dibenzazepine (DBA) chromophores (DBA-COCH2CH2(OCH2CH2)nOCH2CH2CO-DBA, n=0-10) was examined.The photoirradiation of bichromophoric compounds caused either intra- or intermolecular reactions.These reactions were kinetically analyzed by two different methods: the measurement of deactivation processes of the reaction intermediates (excited triplet state of DBA) by nanosecond laser photolysis and the quantitative analysis of the reaction products by GPC.The intramolecular deactivation rate constant, kintra, showed a remarkable chain-length dependence; the maximum kintra value appeared at n=5 and it was found to be 5.9X104 s-1.On the other hand, the intramolecular cyclization rate also depends on the chain length; the maximum quantum yield, φintrad, was given at n=7 (φintrad=0.51).The chain length for the maximum cyclization yield shifted slightly to the longer region than that for the maximum kintra value due to the restriction of the terminal structure (anti-configuration).The results obtained for this reaction system are compared with those obtained for the previously reported polymethylene system and the effect of chain flexibility on the intramolecular ring-closure reaction is discussed.
