Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment

Meihui Yi; Fengbin Wang; Weiyi Tan; Jer Tsong Hsieh; Edward H. Egelman; Bing Xu

doi:10.1021/jacs.2c05491

Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment

Meihui Yi, Fengbin Wang, Weiyi Tan, Jer Tsong Hsieh, Edward H. Egelman, Bing Xu

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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 microenvironment. By phosphorylation and conjugating nitrobenzoxadiazole (NBD) to hydroxybiphenylcarboxylate (BP), we obtained pBP-NBD (1P) as a substrate of both acid and alkaline phosphatases. 1P effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture. 1P enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of 1P by mCRPCs. Cryo-EM reveals the nanotube structures of both 1P (2.4 Å resolution, pH 5.6) and 1 (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.

Original language	English (US)
Pages (from-to)	13055-13059
Number of pages	5
Journal	Journal of the American Chemical Society
Volume	144
Issue number	29
DOIs	https://doi.org/10.1021/jacs.2c05491
State	Published - Jul 27 2022

ASJC Scopus subject areas

Catalysis
Chemistry(all)
Biochemistry
Colloid and Surface Chemistry

Access to Document

10.1021/jacs.2c05491

Cite this

@article{637f727d36c64f7cb1d186fce08bc85a,

title = "Enzyme Responsive Rigid-Rod Aromatics Target {"}Undruggable{"} Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment",

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 microenvironment. By phosphorylation and conjugating nitrobenzoxadiazole (NBD) to hydroxybiphenylcarboxylate (BP), we obtained pBP-NBD (1P) as a substrate of both acid and alkaline phosphatases. 1P effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture. 1P enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of 1P by mCRPCs. Cryo-EM reveals the nanotube structures of both 1P (2.4 {\AA} resolution, pH 5.6) and 1 (2.2 {\AA} 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.",

author = "Meihui Yi and Fengbin Wang and Weiyi Tan and Hsieh, {Jer Tsong} and Egelman, {Edward H.} and Bing Xu",

note = "Funding Information: This work is partially supported by NIH CA142746 (B.X.) and CA252364 (B.X. and J.-T.H.), GM122510 (E.H.E.), K99GM138756 (F.W.), and NSF DMR-2011846 (B.X.). Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",

year = "2022",

month = jul,

day = "27",

doi = "10.1021/jacs.2c05491",

language = "English (US)",

volume = "144",

pages = "13055--13059",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "29",

}

TY - JOUR

T1 - Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment

AU - Yi, Meihui

AU - Wang, Fengbin

AU - Tan, Weiyi

AU - Hsieh, Jer Tsong

AU - Egelman, Edward H.

AU - Xu, Bing

N1 - Funding Information: This work is partially supported by NIH CA142746 (B.X.) and CA252364 (B.X. and J.-T.H.), GM122510 (E.H.E.), K99GM138756 (F.W.), and NSF DMR-2011846 (B.X.). Publisher Copyright: © 2022 American Chemical Society.

PY - 2022/7/27

Y1 - 2022/7/27

N2 - 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 (1P) as a substrate of both acid and alkaline phosphatases. 1P effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture. 1P enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of 1P by mCRPCs. Cryo-EM reveals the nanotube structures of both 1P (2.4 Å resolution, pH 5.6) and 1 (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.

AB - 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 (1P) as a substrate of both acid and alkaline phosphatases. 1P effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture. 1P enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of 1P by mCRPCs. Cryo-EM reveals the nanotube structures of both 1P (2.4 Å resolution, pH 5.6) and 1 (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.

UR - http://www.scopus.com/inward/record.url?scp=85135369810&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85135369810&partnerID=8YFLogxK

U2 - 10.1021/jacs.2c05491

DO - 10.1021/jacs.2c05491

M3 - Article

C2 - 35849554

AN - SCOPUS:85135369810

SN - 0002-7863

VL - 144

SP - 13055

EP - 13059

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 29

ER -

Enzyme Responsive Rigid-Rod Aromatics Target "Undruggable" Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this