The Endo-GeneScreen Platform Identifies Drug-Like Probes that Regulate Endogenous Protein Levels within Physiological...

Area of Science:

• Biochemistry
• Neuroscience
• Drug Discovery

Background:

• Traditional phenotypic drug discovery lacks scalability and mechanistic insight.
• Identifying small molecules that modulate endogenous gene expression is challenging.

Purpose of the Study:

• To develop a high-throughput screening platform, Endo-GeneScreen (EGS), for identifying bioactive small molecules targeting endogenous gene expression.
• To demonstrate EGS's capability in discovering therapeutic candidates for neurodevelopmental disorders.

Main Methods:

• EGS platform development for high-throughput screening.
• Screening for compounds regulating endogenous neuronal Syngap1 expression.
• Characterization of identified drug candidates and their mechanism of action.

Main Results:

• EGS successfully identified small molecules that up-regulate endogenous Syngap1 expression.
• SR-1815, a novel kinase inhibitor, restored SynGAP protein levels and reduced neuronal hyperactivity in Syngap1-haploinsufficient neurons.
• EGS assays accelerated preclinical development and facilitated mode-of-action studies.

Conclusions:

• EGS is a scalable platform for discovering first-in-class bioactive small molecules targeting endogenous protein expression.
• EGS facilitates biological discovery and precision therapeutic development for genetic disorders.
• The identified kinase inhibitor SR-1815 shows therapeutic potential for Syngap1-related neurodevelopmental disorders.