RAC (ASX) Cardioprotection thread

Originally posted by Mason14: ↑

Cardioprotection MoA - Calcium homeostasis

I think that the MoA for cardioprotection is going to be around the regulation of caclium (Ca2+) in cardiomyocytes - potentially the RyR2, SERCA2, CaMKII, NF-kB, and p53 gene networks. Calcium homeostasis is dysregulated in both Anthracycline and Proteasome Inhibitor dosing.

High FTO activity in cardiomyocytes improves calcium handling, while FTO knockdown models demonstrated irregular heartbeats. This may indicate why the FTO inhibitors (brequinar, FB23-2, and Dac51) show a steady decrease in cell viability (increase in cardiomyocyte death) as dose concentration increases (below) - observe the red line on each chart. It could also just be because of increased toxicity generally. A cell model does not provide enough detail to truly understand the relationship between pharmacology and biology of a dynamic organ.

Bisantrene clearly demonstrates improved cardioprotection, while also inhibiting FTO at significantly lower concentrations than the other molecules. I notice a dip in cell viability at the start, which starts to change around 250nM. If my wild speculation is correct, then this could be a sign of Bisantrene being counterproductive at lower concentrations (or just not working as a cardioprotective agent) where it is only inhibiting FTO, and when the cardioprotective concentrations are reached for the MoA, it begins positively influencing calcium homeostasis and providing cardioprotection.

If calcium handling is the MoA for cardioprotection, there are a couple of takeaways:

1. The cardioprotective MoA is enough to buffer the effects of FTO inhibition dysregulation of calcium handling (as well as anthracene) - indicating a significant strength of that pathway
2. If it is not a single pathway, then Bisantrene may be targeting multiple pathways that provide cardioprotection - indicating a truly unique drug
3. If either 1 or 2 are correct, Bisantrene will become very challenging to replace clinically and, of course, commercially

This is highly speculative, but I thought I would put my thoughts up.

@Boffin99 what were your thoughts?

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interesting @Mason14 I had somewhat gone down this path before at exploring dose effect on cardio protection but hit a dead end.

More likely MOA1 + MOA2 = CP and one of these MOAs in combo preserves the ACS part of CPACS.

I am not convinced that CP is FTO dependent based on prior announcements. Inhibitors exists to treat cardiotoxicity gene expressions on your list, but Im not aware of any of them resulting in CPACS.

It is therefore plausible that multiple MOA of CPACS will make it near on impossible to replicate. Also unless proved mechanistically the patent office and Pharma will argue ‘Bisantrene’ is simply cardiac friendly.

Race need to know the MOA, in this case. I believe that they already know but we won’t hear about this until the patent is lodged. This is for commercial reasons and fear of being a takeover target.

Moral of the story we need more data, on how the drug works.

My pure speculation, is Aaron knew the MOA
and this went to Brian for validation. If correct then they should have a fairly good idea whether this would translate to the clinic.

For what it’s worth, I think Bisantrene impacts on metabolism of healthy and tumour cells differently in order to facilitate CPACS.