National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM122510
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
K99GM138756
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
CA142746
米国
National Science Foundation (NSF, United States)
DMR-2011846
米国
引用
ジャーナル: J Am Chem Soc / 年: 2022 タイトル: Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment. 著者: Meihui Yi / Fengbin Wang / Weiyi Tan / Jer-Tsong Hsieh / Edward H Egelman / Bing Xu / 要旨: Bone metastasis remains a challenge in cancer treatment. Here we show enzymatic responsive rigid-rod aromatics acting as the substrates of "undruggable" phosphatases to kill cancer cells in a mimetic ...Bone metastasis remains a challenge in cancer treatment. Here we show enzymatic responsive rigid-rod aromatics acting as the substrates of "undruggable" phosphatases to kill cancer cells in a mimetic bone microenvironment. By phosphorylation and conjugating nitrobenzoxadiazole (NBD) to hydroxybiphenylcarboxylate (BP), we obtained pBP-NBD () as a substrate of both acid and alkaline phosphatases. effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture. enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of by mCRPCs. Cryo-EM reveals the nanotube structures of both (2.4 Å resolution, pH 5.6) and (2.2 Å resolution, pH 7.4). The helical packing of both nanotubes is identical, held together by strong pi-stacking interactions. Besides reporting the atomistic structure of nanotubes formed by the assembly of rigid-rod aromatics, this work expands the pool of molecules for designing EISA substrates that selectively target TME.