Small molecules that control Hes1 oscillation

2015 Fiscal Year Final Research Report

• Project/Area Number: 26560445
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: Kyoto University
• Principal Investigator: Uesugi Motonari 京都大学, 物質－細胞統合システム拠点, 教授 (10402926)
• Co-Investigator(Renkei-kenkyūsha): KAGEYAMA Ryoichiro 京都大学, ウイルス研究所, 教授 (80224369)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 化学プローブ / ケミカルバイオロジー

Outline of Final Research Achievements

Hes1 is a transcriptional repressor that plays an important role in cell differentiation. We previously isolated a potent Hes1 modulator (D8C) through high-throughput screening. A total of 176 D8C derivatives were synthesized and tested for their effects on Hes1-mediated repression. Out of these compounds, JI051 showed a 5-fold improvement in EC50 value as compared to D8C. Our mechanistic analysis revealed that JI051 induces the nuclear export of Hes1 and its corepressor TLE1 with concomitant mitochondrial release of the TLE1 protein regulator, Bit1. Target identification studies highlighted the mitochondrial protein Prohibitin 2 (PHB2) as a target for JI051. The interaction of JI051 with PHB2 appears to increase superoxide production associated with mitochondrial membrane depolarization. These results suggest that JI051 inhibits Hes1 through its PHB2-dependent nuclear export.

Free Research Field

ケミカルバイオロジー