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New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse
Frédéric Stauffer1, Andreas Weiss1, Clemens Scheufler1
1Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
Abstract:
In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.
Insights
New DOT1L inhibitors show promise for treating MLL-rearranged cancers. These compounds target aberrant gene expression by inhibiting DOT1L, demonstrating therapeutic potential in preclinical models.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- MLL-rearranged cancers involve aberrant recruitment of DOT1L to ectopic loci.
- This leads to H3K79 hypermethylation and misexpression of leukemogenic genes.
Purpose of the Study:
- To discover potent DOT1L inhibitors.
- To test the therapeutic principle of DOT1L inhibition in a preclinical cancer model.
Main Methods:
- Structure-guided optimization of a high-throughput screening (HTS) hit.
- In vitro biochemical and cellular assays for potency and target engagement.
- In vivo testing in a mouse tumor xenograft model.
Main Results:
- Discovery of DOT1L inhibitors with subnanomolar potency.
- Compounds achieved good pharmacokinetic exposure in mice.
- Nanomolar inhibition of target gene expression was observed in cells.
Conclusions:
- DOT1L inhibition is a viable therapeutic strategy for MLL-rearranged cancers.
- The developed compounds warrant further investigation in preclinical and clinical settings.
