2. Academic Validation
  3. Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone

Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone

  • J Biol Chem. 2018 May 25;293(21):8285-8294. doi: 10.1074/jbc.RA118.002316.
Amelie Perron 1,  Yoshihiro Nishikawa 2,  Jun Iwata 3,  Hiromi Shimojo 4,  Junichiro Takaya 3,  Kumiko Kobayashi 5,  Itaru Imayoshi 6,  Naasson M Mbenza 3,  Mihoko Takenoya 7,  Ryoichiro Kageyama 4,  Yuzo Kodama 8,  Motonari Uesugi 9
Affiliations

Affiliations

  • 1 Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Uji, Kyoto 611-0011.
  • 2 Department of Gastroenterology and Hepatology, Graduate School of Medicine.
  • 3 Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011.
  • 4 Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Uji, Kyoto 611-0011; Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
  • 5 Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
  • 6 Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
  • 7 Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Uji, Kyoto 611-0011.
  • 8 Department of Gastroenterology and Hepatology, Graduate School of Medicine. Electronic address: kodamayu@kuhp.kyoto-u.ac.jp.
  • 9 Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Uji, Kyoto 611-0011. Electronic address: uesugi@scl.kyoto-u.ac.jp.
PMID: 29523683 DOI: 10.1074/jbc.RA118.002316
Abstract

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 π-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 EC50 of 0.3 μm 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 G2/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.

Keywords

Notch pathway; Prohibitin 2; basic helix-loop-helix transcription factor; cell proliferation; chaperone; chemical biology; pancreatic cancer; small molecule.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117113
    ≥98.0%, Hes1-PHB2 Interaction Stabilizer
  • HY-124484
    99.01%, Hes1-PHB2 Stabilizer