The Endo-GeneScreen platform identifies drug-like probes that regulate endogenous protein levels within physiological contexts

  • Nat Commun. 2025 Dec 9;16(1):10970. doi: 10.1038/s41467-025-65971-x.
Preston Samowitz  1  2 ,  Laszlo Radnai  3 ,  Thomas Vaissiere  1 ,  Sheldon D Michaelson  1 ,  Camilo Rojas  1 ,  Ryan Mitchell  1  2 ,  Murat Kilinc  1  2  4 ,  Austin Edwards  3 ,  Justin Shumate  3 ,  Richard Hawkins  3 ,  Virneliz Fernandez-Vega  3 ,  Timothy P Spicer  3 ,  Louis Scampavia  3 ,  Theodore Kamenecka  3 ,  Courtney A Miller  1  2  3 ,  Gavin Rumbaugh  5  6  7
Affiliations
  • 1. Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
  • 2. The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, FL, USA.
  • 3. Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
  • 4. Merck & Co, Rahway, NJ, USA.
  • 5. Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA. [email protected].
  • 6. The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, FL, USA. [email protected].
  • 7. Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA. [email protected].
PMID: 41366089 DOI: 10.1038/s41467-025-65971-x
Abstract

Traditional phenotypic drug discovery platforms suffer from poor scalability and/or a lack of mechanistic understanding of discovered probes. We address this by creating Endo-GeneScreen (EGS), a high-throughput platform that identifies small molecules that regulate endogenous protein levels encoded by a preselected target gene within disease-modeling contexts. Two initial screens identify >40 validated small molecules that boost endogenous neuronal Syngap1 levels, a gene that causes a neurodevelopmental disorder when haploinsufficient. EGS assays also accelerate preclinical development of drug candidates and facilitate mode-of-action deconvolution studies of orphaned probes. SR-1815 represents a fully validated proof-of-concept candidate from the platform. It is a previously unknown drug-like small molecule multikinase inhibitor that regulates splicing of Syngap1 transcripts. It restores SynGAP protein abundance to wildtype levels and mitigates major cellular consequences of Syngap1 loss-of-function. Thus, the EGS platform promotes identification and development of small molecules that alter the abundance of disease-linked proteins in a translationally-relevant context.

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