Information about AMN 107

[Guest guest]

There was a question or two about AMN 107, the new drug in clinical trial

from Novartis:

Like Gleevec (Glivec) AMN 107 is also a selective inhibitor. AMN 107 is a

selective aminopyridine inhibitor of BCR-ABL (tyrosine kinases (enzymes)

that attach phosphate groups to other proteins, activating them - so that

natural cell death (apoptosis) does not occur=cancer). Because it is

selective, it is less likely to damage surrounding cells, so it isn't really

like a chemotherapeutic drug, but some people think of it as one.

AMN 107 requires a less stringent topological fit to the ATP-binding pocket

in the inactive conformation of BCR ABL. Mutations in ABL, which change the

shape of the binding pocket, have less of an effect on AMN 107 than on

Gleevec (IM) binding. You can picture this like a piece of a puzzle.

Gleevec and AMN 107 fit into the the part of the BCR-ABL enzyme where ATP

would fit (ATP is like the energizer bunny rabbit, it is like a power pack

that supplies energy to the enzyme. This keeps the enzyme in an active

state so it never goes through the natural process of cell death (apoptosis)

and keeps producing more and more cells = cancer). Since AMN 107 fits in

this pocket, ATP cannot fit in the pocket, which causes the cell to die.

Gleevec is more selective to PDGFR (Platelet derived growth factor, one of

the numerous proteins that regulates cell growth and division), KIT then

ABL. Whereas, AMN 107 is more selective for ABL, then KIT then finally

PDGFR. This ability to be more selective for ABL makes AMN 107 at least 25

times more potent than Gleevec. I seem to recall that some of the scientist

and doctors say that most of the side effects we have on Gleevec are because

it is more selective for PDGFR. That is why the theory is we should see

less side effects on AMN 107.

AMN 107 inhibits proliferation and autophosphorylation of 32 of the 33 of

the BCR ABL point mutants. The only exception be the dreaded T315I, for

which there is no drug currently available, but there is something in

development.

Hope this helps, and if you have any questions or need further explanation

and breakdown of what I have written, please do not hesitate to ask.

Cheers, Peace, Love and all good things,

Cheryl-Anne