| Autor: |
Seabrook, Laurence J., Franco, Carolina N., Loy, Cody A., Osman, Jaida, Fredlender, Callie, Zimak, Jan, Campos, Melissa, Nguyen, Steven T., Watson, Richard L., Levine, Samantha R., Khalil, Marian F., Sumigray, Kaelyn, Trader, Darci J., Albrecht, Lauren V. |
| Zdroj: |
Nature Chemical Biology; 20240101, Issue: Preprints p1-11, 11p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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