Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Brachyury is an oncogenic transcription factor driving chordoma growth.
• Targeting brachyury is therapeutically promising but challenging due to its nature as a transcription factor.
• Previous efforts focused on upstream kinases, with afatinib showing potential to modulate brachyury.

Purpose of the Study:

• To develop a novel small molecule inhibitor that directly targets and downmodulates brachyury.
• To explore a structure-based drug design approach for creating potent brachyury modulators.
• To demonstrate the feasibility of direct brachyury modulation for chordoma therapy.

Main Methods:

• Utilized a structure-based drug design approach.
• Employed mass spectrometry and X-ray crystallography for compound development.
• Designed DHC-156 to selectively bind brachyury, eliminating kinase inhibition.

Main Results:

• Developed DHC-156, a small molecule that potently downmodulates brachyury.
• DHC-156 selectively binds brachyury without inhibiting kinases.
• Demonstrated irreversible impairment of chordoma tumor cell growth via post-translational brachyury downmodulation.

Conclusions:

• Direct modulation of brachyury is feasible and therapeutically viable.
• DHC-156 represents a novel scaffold for developing potent brachyury-targeting therapies.
• This approach opens new avenues for treating brachyury-driven cancers like chordoma.