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

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.