Jim:
Lots of good questions......
>>1) How does their combinatorial library seem? Is it primarily carbohydrate based
and is there any problem with specificity of the hits or optimized compounds, if any?<<
For angio..... they have hits, but you've nailed the problem.... they're looking at heparan antagonists, and, while they have compounds that block the interaction with bFGF and VEGF, they also block binding with other growth factors. They have isolated compounds that demonstrate *some* selectivity, but, as of 5 months ago, they needed to go into a second-generation library to find more potent antagonists. They generate extended-scaffold organics. I'm no chemist, but their libraries seem to be respected.
>>Do the hits interact with receptor carbohydrates?<<
I've been assuming that the hits mimic the low-affinity receptor and react with the growth factor.
>>does this seem to be a solid approach? Other combichem libraries are biased
towards small molecule lipophilic organics. I know several excellent libraries of this
latter sort (MRK, other smaller, promising companies), but know of no other that
targets cytokine-like receptor carbohydrates.<<
I worry about specificity and thus toxicity. It's the disclaimer that I live by with RGEN.
>>2) What is known about the specific chemokine targets that are the basis for the
Glaxo collaboration? Has there been any successes here yet? Any press reports on
this, or any relevant management discussion?<<
Just the renewal of the collaboration, to my knowledge. The company seems to be very quiet, very professional. However, all of these guys come from an old RGEN background before splitting for Glycan and subsequently returning. So, they have tons of experience with PF4. My best guess is PF4 or IL-8. I do know that at least one hit with Pfizer made it to advanced preclinical.
>>3) How many troops are working there in the trenches, what does the spirit seem to
be, and how good are the assays?<<
The screening assays are high signal to noise filter retention of 125I-GAG complexed to the growth factor. Formatted for HTS, if you have an inhibitor, you get no retention of iodine. For the angio program, they use a 16 saccharide unit heparan. I get the feel that it's a reliable, straightforward assay. They've only done one animal experiment, using the suboptimal hit, that I know of. Robert D'Amato, corneal angio. It worked, but they need an iterative step or two. Troops? Not enough. We only saw two chemists working on the libraries, and it was indicated that they had done a majority of the work. However, they've been at this a bit longer than most companies. They've generated over 24K compounds.
Cheers! Rick |
