2. Academic Validation
  3. Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins

Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins

  • Nat Chem Biol. 2024 Dec;20(12):1566-1576. doi: 10.1038/s41589-024-01741-y.
Laurence J Seabrook 1,  Carolina N Franco 2,  Cody A Loy 2,  Jaida Osman 3,  Callie Fredlender 2,  Jan Zimak 4,  Melissa Campos 1,  Steven T Nguyen 2,  Richard L Watson 5,  Samantha R Levine 4,  Marian F Khalil 2,  Kaelyn Sumigray 6,  Darci J Trader 2 3,  Lauren V Albrecht 7 8
Affiliations

Affiliations

  • 1 Department of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA.
  • 2 Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
  • 3 Department of Chemistry, School of Physical Sciences, University of California, Irvine, Irvine, CA, USA.
  • 4 Center for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA.
  • 5 Department of Medicine, Division of Pulmonary & Critical Care, University of California, Los Angeles, Los Angeles, CA, USA.
  • 6 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • 7 Department of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA. l.albrecht@uci.edu.
  • 8 Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA. l.albrecht@uci.edu.
PMID: 39414979 DOI: 10.1038/s41589-024-01741-y
Abstract

A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates-glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders.

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