Monthly MycetOS meeting - 25 June 2024

mattodd commented 5 months ago

Time: June 25th (12 noon UK) (Timezones)

The Outlook invite can be found https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/2#issuecomment-1905476888

Location: https://uni-sydney.zoom.us/j/99281549497. In case of failure, use https://ucl.zoom.us/j/99789829423 and in case of double failure use MycetOS meeting teams link

Chair: UCL Minute taker: ErasmusMC Previous meeting: uploaded? Recording of today's meeting: Present: Apologies:

AGENDA AND MINUTES

Screening updates

[ ] @MA-Jjingyi and/or @marijschippers to report on any new data --> @marijschippers internship finished. The data she generated were posted in the spreadsheet. @MA-Jjingyi continued with the in vivo screening, however we ran out of some of the compounds (see below). @ Ma-Jingyi is continuing with the in vitro and in vivo screening.
[ ] Suggestion from May meeting: include in Master List, or elsewhere, shipping and arrival dates. --> @ wwjvdsande will do that
[ ] In May, compounds arrived in Otago. @AndreaOtago to update.

Series 1 - Fenarimols

[ ] @KlementineJBS has added some compounds to a "Desired compounds" page here. Where can the structures be found?
[ ] https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/wiki/Desirable-Compounds-Not-Yet-Synthesised seems to be out of date, can anyone advise if this can be archived or updated?
[ ] @mattodd to capture on these paged desirable compounds identified in forthcoming Fenarimol paper, e.g. meta-substituted derivatives.

Paper update

Updated list of To Dos here.

The paper is almost ready to go. However, the NMR data needs to be sorted. Both @dmitrij176 and Hung finished their thesis and will submit soon. @mattodd will go through all the molecules one more to check if all the donations are acknowledgements

Modelling update

@meh-cyprian to proceed to try to model fenarimol compounds in potential protein target (described https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/68#issuecomment-1546869698 or to clarify what more data are needed. Aim is to better understand the SAR via docking vs homology model of protein. @osmanwa also interested in this area, has been in touch with @wwjvdsande and @mattodd by email, and can report back.

No activity in this area for a long time, so this section will be archived on the wiki and removed from meetings for now. Will be activated again when we find someone who is willing to do this.

Series 2 - Aminothiazoles

@P-Rayner to report on any aminothiazoles his uni has made --> did not attend, hopefully next month an update again
updates from USyd - will likely have new compounds described here and here by next meeting (end of June). Focus is on the thiazole end of the molecule, trying out some dichloro combinations and fused rings. @KlementineJBS will be away from July so probably no compounds after that. --> 18 were made, they will be shipped this week.
Is Wendy's new PhD student willing to do a sweep of the literature on mechanism of action, with support from chemists? can anyone else volunteer? MSc of @eloizidou already are looking into the literature. The new PhD student could also contribute.
@wwjvdsande has created a page to communicate about this more clearly (see here)
Whitgift did visit UCL and new molecules were created. They did create a few molecules for series 2 but might like to switch to series 3. Whitgift need to know what new molecules they need to make for the next semester.

Not addressed directly

[ ] All compounds have been evaluated, including from @eloizidou and @Whitgift? Any updates to the current SAR page?
[ ] @eloizidou to complete latest LCMS/NMR characterisation of Whitgift samples. Has one sample been evaluated in vitro?
[ ] Mechanism of Action. Any clues from literature? Volunteers for student project? Should we measure for synergism with itraconazole (which hits Cyp51).
[ ] @dosreic to try to secure samples related to this paper https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/11 ?

Series 3: Tricyclics/Phenothiazines

@P-Rayner to update on any phenothiazines sent through, state of student notebooks
Have any more phenothiazines been tested at higher concentrations? @MA-Jjingyi @wwjvdsande
@marijschippers or others to report on repeat toxicity tests and efficacy tests for NEU/Curaxin compounds that had promising early results (MYOS626, 627, 628, 631, 632), see here
Series 3 wiki is now up and running at https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/wiki/ --> the "tail" of this series seems to be fixed (based on 10.1021/acs.jmedchem.2c01767 and the weak potency of N-phenethylphenothiazine), but the "head" can be optimized
4 of these NEU/Curaxin compounds screened for toxicity in vivo by @marijschippers were excellently nontoxic (what myos codes?), with minimal larvae death, but one NEU/Curaxin compound showed some toxicity (what myos code?) --> data will be added to the spreadsheet as soon as possible (was this done already?)

Series 5 - Benzimidazoles

@MA-Jjingyi is drafting results into a paper
Andrea is doing some SAR assessments on the benzoxazoles --> the first SAR results are in. Currently some new molecules are tested and then the SAR will be updated.
One compound was very promising in vitro and will move into toxicity screens soon, two have prolonged larval survival
Question of renaming benzimidazoles series 5a and the benzoxazoles series 5b apparently not yet decided - will need volunteers to edit masterlist
@AndreaOtago to update on new benzoxazoles likely to be incoming.
Are there any other labs with related compounds we should contact?

Series 6: ketoximes

@dmitrij176 was putting together a priority list of what would be most useful to test if possible as he would like a few of the earlier compounds to be tested in vivo as single isomers if there is any space in the schedule
Dmitrij is still working on SAR scheme and will share it later

Other

Global Health Priority Box

Paper now published!

any updates on analogues from GSK?
data. MMV1804559 both prolonged larval survival and induced morphological changes in the grains (decreasing their size), however at higher concentrations it was toxic too. Tentatively DYRK1 could be the (novel) target, potentially woronin body? Some preliminary discussion https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/15#issuecomment-1943554945. --> still interested in this compound. Don't know how easy it is to make or get analogues but certainly interesting to look further into this

Kinase Inhibitor Library

Mickey can update on this being written into a paper/share any new results. in vivo testing has been difficult as many compounds in this library are too toxic, will have to try lower concentrations
KCGS library was screened along with compounds of similar classes that were sent by @bebi78, with 6 hits in total
[ ] ACTION link to data / add to masterlist
[x] ACTION @MA-Jjingyi to update spreadsheet with larval toxicity studies if not already done --> The manuscript is almost finalised

Plant Extracts from Nigeria --> this issue is going to be archived.

has @bebi78 succeeded in contacting the relevant people again? --> no reply, decided to archive it for now. There is potentially also a plant extract library in the UK which could be mined.

Dundee DMPK Measurements

Mat has shared some results here but not all compounds were tested
[ ] ACTION @dmitrij176 will put together a diagram of results

AOB

Sporotrichosis project

@wwjvdsande is collaborating with Melissa Xavier from Brazil and will be sharing some samples of drugs

Toxicity column

new column in masterlist gives details on toxicity
[ ] ACTION @wwjvdsande will create a page on the Wiki that describes the methods for determining toxicity
current method is basically to inject larvae and compare death rates to injections with water or PBS

Other

@bebi78 writing up info about niclosamide
CUREID is collecting info about off label drug use
still need a pharmaceutical contact, maybe through the DNDi?

Next meeting

https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/24 SKIPPED DUE TO SUMMER HOLIDAY

MA-Jjingyi commented 5 months ago

Hi, three compounds from series 3, MYOS626, MYOS627 and MYOS628 were used up. and Marij finished her internship. If you want to test them in vivo model this summer, Please send them again. Then I will try to test them later.

MFernflower commented 5 months ago

@lferrins could more of these compounds be send to Wendy's lab for in-vivo screening in the caterpillar model?

LoriRequest

MFernflower commented 5 months ago

@eloizidou https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/wiki/Desirable-Compounds-Not-Yet-Synthesised

wwjvdsande commented 5 months ago

@OpenSourceMycetoma/corecontrib the next monthly meeting will be on 23 July, which is during the summer holidays in the Northern hemisphere. We wondered if there will be enough people going to attend the meeting. Could you put your name behind the question if you are attending yes or no [ ] Yes I will be attending: [ ] No I will not be attending: @wwjvdsande @KlementineJBS

wwjvdsande commented 5 months ago

@OpenSourceMycetoma/corecontrib I added the toxicity data and the extra columns in the spreadsheet

lferrins commented 4 months ago

@lferrins could more of these compounds be send to Wendy's lab for in-vivo screening in the caterpillar model?

I can check on the availability of material - how much would you need?

MFernflower commented 4 months ago

@lferrins five milligrams is the number I remember but tagging @wwjvdsande to verify

MFernflower commented 4 months ago

@mattodd I remember you saying you were in the process of plating a library of compounds you group has made and would give them to another researcher - I have not been in contact with the Rice pathogenic amoeba research lab ( @MOUSEY007 ) for quite some time (after the fenarimol screen that gave negative results) but perhaps you could see if they would be interested in it?

https://vet.purdue.edu/discovery/rice/index.php

I think the TB ones would be the most intersting as one of these pathogenic amoeba (Balamuthia) has a thick cell wall somewhat like that of TB

MA-Jjingyi commented 4 months ago

@lferrins five milligrams is the number I remember but tagging @wwjvdsande to verify

Good morning, @lferrins. Yes, five milligrams are enough.

MFernflower commented 4 months ago

Hi all, I assume the meeting for July is cancelled due to summer vacation of the participating universities?

mattodd commented 4 months ago

Yes - let me add a note to the Issue list.

lferrins commented 3 months ago

@lferrins five milligrams is the number I remember but tagging @wwjvdsande to verify

Good morning, @lferrins. Yes, five milligrams are enough.

Thanks @MFernflower for finding this for me! @MA-Jjingyi we have found them but likely don't have 5mg of all of them. What is the minimum quantity that you need?

MFernflower commented 3 months ago

I just checked our "masterlist" -----> it seems like the original curaxin 137 was not sent in batch of compounds to Wendy??

@mattodd @lferrins @wwjvdsande

I feel like it would be rather important to screen pure curaxin 137 since this is now the main lead for series 3

lferrins commented 3 months ago

I will see if we can find it - however, we don't have to test that compound specifically. The derivative/s with the best activity and selectivity are ultimately the ones that we are most interested in!

MFernflower commented 3 months ago

You are indeed correct. However the current strategy is to try to scaffold hop away from the diacetylcarbazole to a tricyclic core with better metabolic stability ---> see https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/wiki/Desirable-Compounds-Not-Yet-Synthesised

So I feel like curaxin 137 should be screened so we can use it as a baseline to compare the scaffold hops too

@lferrins

On Tue, Aug 6, 2024, 8:24 PM Lori Ferrins @.***> wrote:

I will see if we can find it - however, we don't have to test that compound specifically. The derivative/s with the best activity and selectivity are ultimately the ones that we are most interested in!

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/23#issuecomment-2272392566, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDSUF3OPIXEVGW5I7VLZQFSNHAVCNFSM6AAAAABJ2UTRT2VHI2DSMVQWIX3LMV43OSLTON2WKQ3PNVWWK3TUHMZDENZSGM4TENJWGY . You are receiving this because you were mentioned.Message ID: @.***>

MA-Jjingyi commented 3 months ago

@lferrins five milligrams is the number I remember but tagging @wwjvdsande to verify

Good morning, @lferrins. Yes, five milligrams are enough.

Thanks @MFernflower for finding this for me! @MA-Jjingyi we have found them but likely don't have 5mg of all of them. What is the minimum quantity that you need?

Hi @lferrins . As usual, 3-5 mg is enough. Recently in larvae model testing, MYOS631 and MYOS632 didn't prolong mm55 infected larvae survival.

just let you know that I will go back to China soon. maybe a new worker will test them for you later.

@OpenSourceMycetoma/corecontrib

OpenSourceMycetoma / Monthly-zoom-meetings