Replies to post #142764 on Biotech Values

[vinmantoo]

iwfal

<PPS I also note that I see no reason, in the above example, to believe that these kinds of effects (slow-one-subtype, speed-another-subtype) should be limited to just direct kinase inhibitors. Anything that acts on a kinase pathway (e.g. HSP90 inhibitors) could, in theory, do the same thing since it appears to be inherent in the complex control loop interaction of the kinases.>

One can't disagree with your comment as a general point. However one can easily make the point that high specificity of a treatment could be a negative rather than the Holy Grail it as been touted to be. I believe someone has already made this point on board regarding kinase inhibitors. I will venture that HSP90 inhibitors will have that same benefit of lack of specificity as they modulate a large variety of proteins.

[biomaven0]

What I don't understand is how Zelboraf, which is supposed to be specific to a mutated BRAF, and inert in wild type, causes any effect in in a RASm tumor with, presumably, wt BRAF?

What seems to be happening is that the drug binds to mutated BRAF (or possibly wt BRAF) and then the BRAF/drug complex in the presence of mutated RAS dimerizes with CRAF to transactivate CRAF . So it's not a traditional off-target effect (drug binding to the wrong target); rather it's a kind of off-pathway effect when there are other pre-existing mutations around. Presumably a different BRAF inhibitor with a different shape might not have the same effect.

There's a nice keynote address by Yale's Schlessinger (who co-founded Sugen and then Plexxikon) available on the AACR site from 2 years ago that explains the detailed molecular mechanics of how RTK activation occurs. He repeated and updated the lecture this year, but it's not available without a membership (I haven't seen the new one). His new company (Kolltan) is trying to take advantage of this deeper understanding, and if he is successful, I suspect this sort of accidental transactivation would not occur and the drug would also be much less resistant to mutations).

Peter

[genisi]

from previous conversations - with genesi or you I believe

#msg-54584465 and the following emails :)