Molecular mechanism of action (mmoa) investigations

[cdsouthan]

I would guess there is a consensus on the importance of pursuing these across our series (but crucially, comparatively with other external leads, at least some of which should have validated targets). However, AWAK, capacity/resources for this within the primary OSM collaborative network are limited. There is some basic stuff like varying pre-incubation to get a kill time but not much else we could expect to get done. Omics is obviously the way to go in the first instance with target mutants as second pass. As ever, this will boil down to who is prepared to help us out with what and when. Since the Creek Lab declared on twitter had used metabolomics to elucidate the mechanism of action for 100 antimalarial compounds, they would seem prime candidates. It would be great to get transcriptomics and proteomics done in // for which some other groups might come in the frame for.

[mattodd]

Relevant paper and companion paper. Thanks for the alert, Chris. Nice paper, good approach. I have emailed Darren (and Stuart Ralph (Series 1 OSM'er)), because he's on the same landmass (I don't know why this matters) but crucially people should feel free to approach others, autonomously, for this kind of analysis/input. I don't scale efficiently. We can ship compounds to interested laboratories. We need MoA work on S1, S3, S4.

[cdsouthan]

Understood, but rather than an e-mail splurge between many parties how about as follows

a) I can frame our mmoa wish list in moderate detail and get anyone on the project who's interested to OK it. We then simply draw the attention of any groups in the frame to the open document, by tweet even.

b) We make clear our enthusiasm for anyone to pick up, but ask them to openly declare some level of commitment to avoid direct duplication and justify sample shipping (actually independent replication would be icing on the cake but we'd need to be sensitive about this)

Its frustrating but another worthy supplier I engaged with did not respond to the idea of synthesizing our frontrunners for sale. This would make things easier for external pick-up, but I'll keep trying

[MedChemProf]

@cdsouthan @mattodd I was planning on re-engaging my contact at the Broad Institute in Cambridge, MA, USA regarding testing OSM-W-272 (MMV639565) in a Target ID experiment (evolve in vitro drug resistance to MMV639565, then sequence the resistant parasites to see if they can identify mutations in the target of the compound). It is a holiday week here at the moment, but I will contact them again on Monday unless someone has any objections.

[mattodd]

Sounds good, @MedChemProf . If they're willing to do that, that's a very useful input. It might make sense to do the experiment in parallel with a frontrunner compound too, though, such as one of the known in vivo actives? See if that can be done for not much more effort, and we could ship it.

@cdsouthan yes, absolutely. It can help to reach out to strategic people using traditional routes, but point them to a public-facing resource as soon as possible. You should frame the issue (for newbies) wherever you like, though Github is pretty useful since we can edit/tweak/add/comment. Obviously mirror on your blog if you like.

MoA on Series 1 interesting for obvious reasons. Series 3 is an funny one. We have not yet found a compound better than the hit. But it's a lovely hit, and is not PfATP4.

[MFernflower]

This would be amazing if we could frame a moa on the s4 drugs. ATP4 is most likely but i wonder if theres another sodium channel were hitting?

[cdsouthan]

Quite so. One of the key strengths of OMICs profiling is hypothesis neutrality. Note that even within what looks like an SAR series, any analogue or the lead itself could be doing a "target shift" (e.g. showing a specifically increased cross-reactivity against a paralogous protein that enhances the IC50 kill factor). This is what target-centric screening will usually try to design "out" - but sometimes "in" (i.e. dual inhibitors). Thus we cannot assume the S4 front runners will have the same PfATP4 specificity for their overall mmoa , ipso facto their omics profiles could be different (within the precision limits of the experiment).

[MFernflower]

Sounds epic but who is going to do the testing? Would be awesome if we could get someone to do it pro bono?! @cdsouthan @mattodd

[mattodd]

Good news. Following an email inquiry, Darren Creek has kindly agreed to perform a metabolomics analysis on a few compounds to investigate MoA, in line with the paper linked above. Thanks for the suggestion @cdsouthan

The Sydney lab will submit a few mg of representative compounds from Series 1, 3 and 4 for this analysis. We'd envisage results being available sometime over the next two months or so.

Any suggestions for which are the most representative compounds gratefully received. For Series 1 I'd suggest OSM-S-5 and one of the "near neighbour" set. For Series 3, there's only really one choice - the original hit. For Series 4 I'd suggest racemic MMV669844, which is actually MMV897709 (recently made in Sydney).

@alintheopen @edwintse assigning to one/both of you to dig out and vial. Darren needs a couple of mgs of each, sent to him at the publicly available address: 399 Royal Parade (rear access via Mile lane), Parkville, Vic, 3052, Straya.

I believe Darren will be fine with 4 compounds. Are there any others that MUST be sent? Darren has indicated he'll be happy to have raw data deposited in the public domain as soon as available.

[MFernflower]

I would def send off the s4 dimethylamime @mattodd

[cdsouthan]

Good news but, AWAK, to be methodologically rigorous (so when would be ever be otherwise :) we should/must add closest chemotype matches with very low activity as internal controls i.e. that would make 8 (+ artemesin?) I would have thought the DC and Syd teams could get a paper out of the exercise especially if they finesse the data sets with time courses for example. Clearly its up to them to decide capacity, but if they can expand to one or two independent PfATPase leads that could solidify a potential paper

[mattodd]

Excellent point, Chris, thanks. Yes, we need to include controls for each. Finding inactives in Series 3 will not be a problem...

[MFernflower]

@mattodd S4 inactive should be easy too. Just make something with no RHS para group

[mattodd]

This was just my little joke @MFernflower . Series 3 was an extraordinary campaign because everything that was tried was essentially inactive. The wiki is woefully out of date so this is not clear.

[MFernflower]

Understood. Quite an oddball hit

[alintheopen]

Hi all, attached are the compounds we plan to send off on the first day back in Jan. Four actives and four inactives from each type of OSM compound. Does the team think it is worth sourcing some of KAE609 (Novartis compound) to include in this screen?

[MFernflower]

Looks great!

On Dec 15, 2016 11:47 PM, "alintheopen" notifications@github.com wrote:

Hi all, attached are the compounds we plan to send off on the first day back in Jan. Four actives and four inactives from each type of OSM compound. Does the team think it is worth sourcing some of KAE609 (Novartis compound) to include in this screen? [image: compounds 161216] https://cloud.githubusercontent.com/assets/2626599/21251951/e75fcbcc-c3a6-11e6-99f3-896427aabfcb.png

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[mattodd]

Including KAE609 is a good idea since this is an independent means of testing whether these molecules possess the same MoA, beyond the ANU ion regulation assay (which is phenotypic). Problem: we don't have any. I wonder if there is any of this molecule already in Melbourne. Not a search we can do, yet.

[MFernflower]

Dug up a synth route for cipargamin... Doesnt look too bad but SM is costly. https://newdrugapprovals.org/tag/cipargamin/

On Dec 16, 2016 12:16 AM, "Mat Todd" notifications@github.com wrote:

Including KAE609 is a good idea since this is an independent means of testing whether these molecules possess the same MoA, beyond the ANU ion regulation assay (which is phenotypic). Problem: we don't have any. I wonder if there is any of this molecule already in Melbourne. Not a search we can do, yet.

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[mattodd]

Oh, no, we'd buy or request it. Novartis might donate, but it'd be quicker if we could source a few mg from somewhere close to the Creek Lab. There is a chance, of course, that Darren may have some, so I'll check that first.

On 16 December 2016 at 16:25, MFernflower notifications@github.com wrote:

Dug up a synth route for cipargamin... Doesnt look too bad but SM is costly. https://newdrugapprovals.org/tag/cipargamin/

On Dec 16, 2016 12:16 AM, "Mat Todd" notifications@github.com wrote:

Including KAE609 is a good idea since this is an independent means of testing whether these molecules possess the same MoA, beyond the ANU ion regulation assay (which is phenotypic). Problem: we don't have any. I wonder if there is any of this molecule already in Melbourne. Not a search we can do, yet.

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