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<p>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-<i>GeneScreen</i> (<i>EGS</i>), 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 <i>screens</i> identify &gt;40 validated small molecules that boost endogenous neuronal <i>Syngap1</i> levels, a gene that causes a neurodevelopmental disorder when haploinsufficient<i>. EGS</i> 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 <i>Syngap1</i> transcripts. It restores SynGAP protein abundance to <i>wildtype</i> levels and mitigates major cellular consequences of <i>Syngap1</i> loss-of-function. Thus, the <i>EGS</i> platform promotes identification and development of small molecules that alter the abundance of disease-linked proteins in a translationally-relevant context.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月9日

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  • Preston Samowitz,
  • Laszlo Radnai,
  • Thomas Vaissiere,
  • Sheldon D. Michaelson,
  • Camilo Rojas,
  • Ryan Mitchell,
  • Murat Kilinc,
  • Austin Edwards,
  • Justin Shumate,
  • Richard Hawkins,
  • Virneliz Fernandez-Vega,
  • Timothy P. Spicer,
  • Louis Scampavia,
  • Theodore Kamenecka,
  • Courtney A. Miller,
  • Gavin Rumbaugh

摘要

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.