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
  • 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. [email protected].
  • 8. Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA. [email protected].
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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