JI051
目录号 : GC34635JI051是一种Hes1-PHB2相互作用稳定剂,能够与癌症相关蛋白伴侣prohibitin2(PHB2)相互作用,通过抑制Notch下游效应基因Hes1来诱导细胞周期停滞。具有抗肿瘤作用。
Cas No.:2234281-75-3
Sample solution is provided at 25 µL, 10mM.
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JI051 is a stabilizer for the Hes1-PHB2 interaction, interacts with a cancer-associated protein chaperone prohibitin 2 (PHB2), induces cell-cycle arrest by inhibiting the Notch downstream effector gene Hes1. Anti-cancer activity[1].
JI051 causes G2/M cell-cycle arrest[1].JI051 (0.1-10 µM, 24 hours) significantly inhibits cell proliferation of HEK293 cells, with an EC50 of 0.3 μM[1]. Cell Proliferation Assay[1] Cell Line: HEK293 cells
[1]. Perron A, et al. 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.
Cas No. | 2234281-75-3 | SDF | |
Canonical SMILES | O=C(NCCC1=CC=CC=C1OCC)/C=C/C2=CNC3=C2C=CC=C3OC | ||
分子式 | C22H24N2O3 | 分子量 | 364.44 |
溶解度 | DMSO : 125 mg/mL (342.99 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.7439 mL | 13.7197 mL | 27.4394 mL |
5 mM | 0.5488 mL | 2.7439 mL | 5.4879 mL |
10 mM | 0.2744 mL | 1.372 mL | 2.7439 mL |
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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.PMID:29523683DOI:PMC5971435
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.