KangpingL
commented
8 months ago We have screened 2 pyrroldines...
... and both of them showed no significant binding. For pyridines...
for reference
...it seems that N at highlighted position is more tolerated - but still need to explore other postions.
(source of data #1 )
The latest SPR data from Shabbir (received 19th Jan 2024) is attached/below (@KangpingL please add data here, as well as your slides from the meeting held Jan 22nd).
(Assay used has not changed since the previously-measured data, i.e. comparable. Data also contains repeats of previously-measured compounds, so comparisons possible.)
Conclusions/next steps:
1) We should explore more halogenation on the southeast aromatic ring. 2) A simple acrylamide warhead in the southwest is still interesting. 3) Can simple akyl chains be accommodated in that position? If yes, we can use as the attachment point for a PROTAC (e.g. hexylamines like this) or as a means to do a pulldown experiment (which would potentially help to identify other protein binders of WDR91). Shabbir is interested in this question, too, experimentally. 4) @KangpingL to complete the currently-remaining targets (especially the three remaining FEP-predicted structures) by early Feb. 5) @KangpingL to check whether any targets/intermediates are now commercially available (which were not before). 6) @Santha-SGC was interested in the use of simple pyrrolidine in the southwest. @KangpingL wasn't that made? 7) To help solubility @KangpingL to make sure we have explored all possible pyridines (as replacements for phenyls). 8) Should we consider developing an NMR binding assay? We'd need a sample of protein and a fluorinated binder (ideally CF3) - KPL34 and KPL35 contained this group but were not active, unfortunately. Can do NMR evaluation at UCL.