Biotech Values

[poorgradstudent]

Re: Pan / Isoform specific inhibition

Only after understanding the targets better, and their clinical profiles better do they start to focus on isoforms or narrower targets. This could be a case in the future. Almost all examples you gave started with pan-inhibition at first.

I'd be interested in that history.

I suspect that, at least for development before the human genome project, likely contributors to pan-inhibition included a poor ability to identify and define isoforms / variants and limited chemistry capability to target specific isoforms.

For the former, I remember in the 90s that there would be strings of papers purporting to identify / clarify whether a gene was expressed as isoforms, if some protein products were from one gene or two, etc... Much of this had to do with the fact that we didn't have the genome sequenced and limited resolution of protein characterization technology (amino acid quantitation / sequencing versus today's mass spec resolution).

As for the latter, I recently read a paper on kinase inhibition where the authors were noting that "conventional" wisdom not too long ago presumed highly selective inhibition of kinases would be a bit of a lost cause due to their similar ATP-binding / catalytic pockets.


Just seems to me that pan-inhibition at our stage of technology, especially for a class of enzymes where we *know* there are distinct players, seems a bit anachronistic.