Related Experiment Video
Updated: Jun 26, 2025
Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Towards the Targeted Protein Degradation of PRMT1
Poppy L Martin1, Francisco Javier Pérez-Areales1, Shalini V Rao2
1Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom.
Abstract:
Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. The incidence of the latter two events may be associated with inhibition-driven pharmacology as a high and sustained concentration of inhibitor is required for therapeutic effect. The degradation of PRMT1 using a proteolysis targeting chimera (PROTAC) may be superior to inhibition as proceeds via event-driven pharmacology where a PROTAC acts catalytically at a low dose. PROTACs containing the same pharmacophore as GSK3368715, combined with a motif that recruits the VHL or CRBN E3-ligase, were synthesised. Suitable cell permeability and target engagement were shown for selected candidates by the detection of downstream effects of PRMT1 inhibition and by a NanoBRET assay for E3-ligase binding, however the candidates did not induce PRMT1 degradation. This paper is the first reported investigation of PRMT1 for targeted protein degradation and provides hypotheses and insights to assist the design of PROTACs for PRMT1 and other novel target proteins.
Insights
Targeted protein degradation using proteolysis targeting chimeras (PROTACs) offers a potential advantage over direct inhibition for targeting protein arginine methyltransferase 1 (PRMT1) in cancer therapy.
Area of Science:
- Oncology
- Chemical Biology
- Drug Discovery
Background:
- Targeting protein arginine methyltransferase 1 (PRMT1) is a promising strategy for cancer treatment.
- The first PRMT1 inhibitor, GSK3368715, faced early termination in clinical trials due to lack of efficacy and toxicity, potentially linked to inhibition-driven pharmacology requiring high drug concentrations.
- Targeted protein degradation via PROTACs may offer an alternative, utilizing event-driven pharmacology at lower doses.
Purpose of the Study:
- To investigate the potential of PROTACs for targeted degradation of PRMT1 as a therapeutic strategy.
- To synthesize and evaluate PRMT1-targeting PROTACs incorporating the GSK3368715 pharmacophore and E3-ligase recruiters (VHL or CRBN).
- To explore hypotheses and insights for designing effective PRMT1 PROTACs.
Main Methods:
- Synthesis of PROTACs containing the GSK3368715 pharmacophore and VHL or CRBN E3-ligase binding motifs.
- Assessment of cell permeability and target engagement using downstream PRMT1 inhibition effects.
- Evaluation of E3-ligase binding using NanoBRET assays.
Main Results:
- Selected PROTAC candidates demonstrated suitable cell permeability and target engagement.
- NanoBRET assays confirmed binding to VHL or CRBN E3-ligases.
- However, the synthesized PROTACs did not induce PRMT1 degradation.
Conclusions:
- This study represents the first investigation into targeted protein degradation of PRMT1.
- While PROTACs showed target engagement, PRMT1 degradation was not achieved, indicating challenges in current design strategies.
- The findings provide valuable insights for future PROTAC design targeting PRMT1 and other proteins.
Related Concept Videos
02:58Regulated Protein Degradation
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
02:18The Proteasome
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
02:51mRNA Stability and Gene Expression
Cis-acting Elements involved in mRNA stability
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:32Export of Misfolded Proteins out of the ER
02:31Nuclear Export of mRNA