I don't really know what you are trying to say, mate. FTO is the...

I don't think Topo2 inhibition ever had a part to play in the clinical success of Bisantrene, but no one can know that.

Ametantrone displayed better preclinical efficacy than Bisantrene as an anthracycline, but showed virtually no response in humans (1PR in 20 patients; below). Bisantrene demonstrates better response than Doxorubicin in cohorts of AML patients. You can't explain that phenomena with the topo2 model.



https://link.springer.com/article/10.1007/BF00170762

I don't really know what you are trying to say, mate. FTO is the fat mass and obesity associated protein that is expressed aberrantly in some cancer types, and bisantrene is a drug that fits neatly into a pocket on the FTO molecule preventing it from demethylating m6A.

The IC50 value for FTO inhibition and topo2 inhibition are dose-dependent, where the IC50 value for FTO is far less than topo2. There is a certain concentration required to inhibit FTO (which is dramatically less than topo2), meaning there is not much drug required for its primary function. The more days in a row that you have an adequate amount of Bisantrene in an organism, the longer duration that the FTO molecule will be inhibited.

Synergy is a big part of it, but there are multiple hallmarks of cancer - foundational principles, if you will. Epitranscriptomic regulators (methylators and demethylators) regulate the genetic environment which has a downstream impact on cellular function. They are essential to cellular activity. Cancer aberrantly expresses these regulators which drastically alters cellular function to adopt the hallmarks of cancer. Chemoresistance is a factor, but so are energy metabolism, proliferation, invasion, and metastasis that are also massively influenced by FTO and, as such, an FTO inhibitor.




FTO is involved in the response. Bisantrene has established efficacy as a single agent of around 40% in AML patients. Nothing has changed.