Notch inhibitor screening reveals an unexpected HES1 heterodimer.

Notch signaling plays critical roles in cancer progression, motivating efforts to identify inhibitors of this pathway. Perron et al. report a small-molecule screen intended to discover compounds that could interfere with the downstream transcription factor HES1. Target validation of their compounds unexpectedly identified a novel HES1-interacting protein, prohibitin 2. This highlights a new mechanism to block Notch signaling and prompting further exploration of HES1 biology.