Cardioprotection thread, page-506

Yes to all of them. I suppose you could be a little more specific on the last, mate.

It appears the knockdown/inhibition of FTO (promoting methylation of m6A) synergises with 3 different cardiotoxic drug classes so far. Based on the central role of FTO for cellular function, I presume this effect will extend to many more cardiotoxic drug classes.

There is actually a little more to it, which solidifies the findings. An increase in METTL3 expression (which increases m6A methylation rates) is a driver of cardiotoxic synergy in DOX and Cyclophosphamide treated HCM. Increased methylation of m6A can be achieved via increasing writers (eg. METTL3) or decreasing/inhibiting demethylators (FTO). Using FTO inhibitor/knockdown models decreases the demethylation of m6A, meaning there is hypermethylation of m6A in HCM.

FTO inhibitor = ↓ demethylation = ↑ methylation

METTL overexpression = ↑ methylation

That would mean there are now 4 drug classes shown to be sensitive to m6A methylation rates in cardiomyocytes: anthracyclines, proteasome inhibitors, TKI inhibitors, and alkylating agents. It’s up to investors whether they decide to include antimetabolites like clofarabine, fludarabine, and Ara-C.