2. Academic Validation
  3. The Endo-GeneScreen platform identifies drug-like probes that regulate endogenous protein levels within physiological contexts

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

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. gavinrumbaugh@ufl.edu.
  • 6 The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, FL, USA. gavinrumbaugh@ufl.edu.
  • 7 Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA. gavinrumbaugh@ufl.edu.
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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