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Old 12-07-2013, 07:19 PM   #6
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Join Date: Oct 2013
Posts: 468
Re: HKI-272 for HER2-Positive Breast Cancer and Brain Metastases

I did research on HKI-272 and learned a lot. Ill have to reread the articles as it is very complicated. It involves understanding the dynamics of the Her1 and Her2 receptors.

HKI-272 blocks the epidermal growth factor receptor and the Her2Neu receptor. Also the Her4 receptor but I dont know the exact significance of this. In many ways it is like Lapatanib. It blocks EGFR, it blocks the Her2Neu receptor and it gets into the brain. Like Lapatanib it causes definite diarrhea in a fairly large percentage of those taking it. Nerotinib also causes nausea, vomiting,
fatigue and appetite loss. The clinical studies with the drug are just starting so there isnt too much info yet.
The dosage probably will be 240mg daily and the Maximum Tolerated Dose is about 320mg daily. The dose limiting side effect is diarrhea.

So far its exactly like Lapatanib. Yet there is a big difference between the drugs. This is where the chemistry comes in and makes the situation complicated.
Simply put, Nerotinib binds much more strongly to the active site of the HER1 or Her2 (the ATP binding pocket)
than Lapatanib does. Nerotonib forms a strong, permanent covalent bond (this is chemistry of course) where Lapatanib forms much weaker Hydrogen bonds.
Therefore Nerotinib should act more strongly.

The problem with the Her1 and Her2 receptors is that they mutate and once they mutate, Lapatanib doesnt really work anymore. Because of the stronger chemical bond that Nerotinib forms, it is hoped it will be effective in those mutated situations where Lapatanib is not.

There is one mutation in the Her1 and Her2 receptor that is particularly troublesome. It is called the T790 mutation. Once this T790 mutation occurs Lapatanib loses its effectiveness. Hopefully Nerotinib wont because of the stronger chemical bond.

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