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Updated: Jun 12, 2026
A Detailed Protocol for Characterizing the Murine C1498 Cell Line and its Associated Leukemia Mouse Model
Published on: October 14, 2016
A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models
Xufen Yu1,2, Dongxu Li3,4, Jithesh Kottur1,2
1Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5-degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel–Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers.
Insights
Pharmacological degradation of WD40 repeat domain protein 5 (WDR5) offers a new cancer therapy. A novel WDR5 degrader, MS67, effectively suppressed tumor growth in preclinical models, outperforming traditional protein-protein interaction inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Structural Biology
Background:
- Interactions of WD40 repeat domain protein 5 (WDR5) with partners like MLL and c-MYC are crucial for cancer development.
- Existing inhibitors targeting WDR5 protein-protein interactions (PPIs) show limited efficacy in cancer treatment.
Purpose of the Study:
- To explore pharmacological degradation of WDR5 as a therapeutic strategy for WDR5-dependent cancers.
- To design and validate a novel WDR5 degrader using structure-based drug design.
Main Methods:
- Structure-based drug design to identify a WDR5 degrader.
- Determination of high-resolution crystal structures of WDR5-degrader-E3 ligase ternary complexes.
- In vitro and in vivo evaluation of the degrader's antitumor activity and selectivity.
Main Results:
- An effective WDR5 degrader, MS67, was identified and characterized.
- MS67 demonstrated potent and selective WDR5 depletion, surpassing PPI inhibitors in suppressing WDR5-regulated gene transcription and protein binding.
- MS67 inhibited cancer cell proliferation and suppressed tumor growth in MLL-rearranged acute myeloid leukemia models with good tolerability.
Conclusions:
- Pharmacological degradation is a viable therapeutic strategy for WDR5-dependent tumors.
- Structure-based design is effective for developing potent WDR5 degraders.
- MS67 shows promise as a novel therapeutic agent for specific cancers.
