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Small-molecule screening yields a compound that inhibits the cancer-associated
transcription factor Hes1 via the PHB2 chaperone
#MMPMID29523683
Perron A
; Nishikawa Y
; Iwata J
; Shimojo H
; Takaya J
; Kobayashi K
; Imayoshi I
; Mbenza NM
; Takenoya M
; Kageyama R
; Kodama Y
; Uesugi M
J Biol Chem
2018[May]; 293
(21
): 8285-8294
PMID29523683
show ga
The transcription factor Hes family basic helix-loop-helix transcription factor 1
(Hes1) is a downstream effector of Notch signaling and plays a crucial role in
orchestrating developmental processes during the embryonic stage. However, its
aberrant signaling in adulthood is linked to the pathogenesis of cancer. In the
present study, we report the discovery of small organic molecules (JI051 and
JI130) that impair the ability of Hes1 to repress transcription. Hes1 interacts
with the transcriptional corepressor transducing-like enhancer of split 1 (TLE1)
via an interaction domain comprising two tryptophan residues, prompting us to
search a chemical library of 1,800 small molecules enriched for indole-like
?-electron-rich pharmacophores for a compound that blocks Hes1-mediated
transcriptional repression. This screening identified a lead compound whose
extensive chemical modification to improve potency yielded JI051, which inhibited
HEK293 cell proliferation with an EC(50) of 0.3 ?m Unexpectedly, using
immunomagnetic isolation and nanoscale LC-MS/MS, we found that JI051 does not
bind TLE1 but instead interacts with prohibitin 2 (PHB2), a cancer-associated
protein chaperone. We also found that JI051 stabilizes PHB2's interaction with
Hes1 outside the nucleus, inducing G(2)/M cell-cycle arrest. Of note, JI051
dose-dependently reduced cell growth of the human pancreatic cancer cell line MIA
PaCa-2, and JI130 treatment significantly reduced tumor volume in a murine
pancreatic tumor xenograft model. These results suggest a previously unrecognized
role for PHB2 in the regulation of Hes1 and may inform potential strategies for
managing pancreatic cancer.
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