Similarity of Series 4 Compounds to KAI407 #147

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mattodd opened this Issue Feb 1, 2014 · 6 comments

2 participants

@mattodd
OpenSourceMalaria member

This paper from Novartis/Scripps/MMV describes a compound (KAI407) effective against a model of P. vivax:

http://aac.asm.org/content/early/2013/12/17/AAC.01927-13.abstract

There are obvious similarities (gut-feeling, not quantified or substantiated) between this compound and OSM's Series 4:

novartis comparison

The known SAR is shown in more detail on the Series 4 wiki, in particular what is known of transposing ring nitrogens and the pendant chain on the pyrazine ring: http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series

Action here is for Mat Todd to contact both MMV and Novartis to check whether some Series 4 compounds have been evaluated in this assay, and if not whether they ought to be.

ELN entry on this, including strings: http://malaria.ourexperiment.org/triazolopyrazine_se/8912

@mattodd mattodd was assigned Feb 1, 2014
@mattodd
OpenSourceMalaria member

This dovetails with a recent update from @cdsouthan on two "similar" compounds that have emerged from Pubchem in which there is also a side chain transposition, in essence showing that the overlay can indeed be similar.
http://cdsouthan.blogspot.com.au/2013/12/searching-triazolopyrazines-for-open.html

@mattodd
OpenSourceMalaria member

Update/Answer - From Paul Willis by email March 5th: Posted to ELN also here: http://malaria.ourexperiment.org/triazolopyrazine_se/8912

These Novartis compounds that bear some similarity to OSM's Series 4 do not appear to hit PfATP4 (the suspected target of Series 4) – i.e. it has been evaluated for this. Data in the Novartis Nature paper [10.1038/nature12782] shows the MOA of the compounds is PI4K. There is also data in the paper (Extended Data Figure 5A) which tests a PfATP4 inhibitor against PI4K mutants, showing no cross resistance, suggesting a different MOA. From the paper, imidazopyrazines KDU691 and KDU751 are active against Py liver schizonts. We now have data (spreadsheet attached to the ELN post) showing the OSM compounds MMV669844 and MMV670944 are v weakly active against Pb liver schizonts (and a big difference from blood potency). Novartis will be unaware which OSM Series 4 compounds have been tested as MMV coordinates the screening of non-Novartis compounds in these screens.

To date, there appears good evidence that the OSM series does not share the same mechanism as the Novartis compounds highlighted: The Novartis imidazopyrazines are reported active against all liver stages in several Plasmodium species, including hypnozoites. For completeness this month, the two OSM compounds will be progressed into the Pc hypnozoite assay mentioned in the Novartis paper.

Keeping this issue open for the moment, since these data need to be added to ELN under "biological evaluation" and wiki needs to be updated, after which issue can be closed.

@cdsouthan

This tallies with som 3D overlays I did between MMV670945 and KA1715 indicating a marked shape difference. I'll see if I can get the pictures up in a blog post. Its still best to complete the reciprocal screening matrix to nail down the SAR divergence though.

@mattodd
OpenSourceMalaria member

More analysis from Chris at http://cdsouthan.blogspot.se/2013/12/searching-triazolopyrazines-for-open.html that suggests compounds overlay poorly. Chris - this is a personal thing, but to me the overlay looks pretty good. I suppose you need to see it in 3D?

@cdsouthan

Interesting and fine by me. My 3D chemistry cognisence is only modest and these analyses can always be extended in different algorithmic ways, more conformer sampling and expanding the series. AWAK // reciprocal cross-screening, including against purified PfATP4, is essential to confirm/refute.

@mattodd
OpenSourceMalaria member

Linked on wiki
http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Other_Sources_of_Compounds_Relevant_to_this_Series
so this will be covered in the first Series 4 paper, but this issue can be closed now.

@mattodd mattodd closed this Dec 10, 2014
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