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Title | Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment. |
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Journal, issue, pages | J Am Chem Soc, Vol. 144, Issue 29, Page 13055-13059, Year 2022 |
Publish date | Jul 27, 2022 |
Authors | Meihui Yi / Fengbin Wang / Weiyi Tan / Jer-Tsong Hsieh / Edward H Egelman / Bing Xu / |
PubMed Abstract | 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. |
External links | J Am Chem Soc / PubMed:35849554 / PubMed Central |
Methods | EM (helical sym.) |
Resolution | 2.2 - 2.4 Å |
Structure data | EMDB-26962: Cryo-EM of self-assembling compound pBP-NBD EMDB-26963: Cryo-EM of self-assembling compound BP-NBD |
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