Ann: Expanded Heart Protection Discovery for Zantrene, page-165

You are most certainly correct.

There are now 14 different anti-cancer drugs that have been shown to synergise with either Zantrene or an FTO inhibition/knockdown model. A number of drugs on this list are cardiotoxic including anti-PD1s, TKIs, anthracyclines, Alkylating agents, Antimetabolites, and Proteasome inhibitors, which can be combined and sold completely separate to Zantrene for millions and even billions of dollars. The possibilities are quite literally endless, and we have the only FTO inhibitor that can decrease intracellular demethylation AND provide cardiac protection.



What I particularly like about the data that is coming out regarding the cardioprotection is the similarities seen in the cardiomyocyte survival. Looking below, it is very encouraging to see that the same concentration of Zantrene (1000nM) is providing a 30% improved in cell survival after treatment with two different cardiotoxic agents. At 15% of the MTD, that lands the dosing regimen somewhere around 37.5 to 45 mg/m2, which is around what I expect the FTO inhibitory dose to be. Also, this dose has demonstrated almost no haemotological toxicity in a phase 1 clinical trial (below).





I am absolutely not a biological scientist here, but from what I can tell, each drugs mechanisms of action for cardiotoxicity is slightly different. Anthracycline-induced cardiotoxicity involves Top2 dependent and independent mechanisms (1), while proteasome inhibitors cause proteasome impairment leading to cardiotoxicity (2). Additionally, Zantrene has shown clinical synergy and seemingly improved cardiac safety when used in combination with Cytarabine in heavily pretreated with anthracycline, poor prognosis AML children. I cannot find the mechanism of cardiac damage with Cytarabine (or Antimetabolites), though I suspect that because this class of drugs target a different biological system, the mechanism likely may be slightly different to anthracyclines and proteasome inhibitors. I think it is important to point out that these mechanisms of action may be different because it highlights that irrespective of the specific mechanism causing cardiac damage, Zantrene is demonstrating that it can protect the heart from these chemotherapeutic agents. What that mechanism might be, I have no idea, but it is important to consider as RAC begin to move into testing other cardiotoxic drugs synergism and cardioprotection with Zantrene.

1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080657/
2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312996/