Monthly MycetOS meeting - 26 March 2024

wwjvdsande commented 8 months ago

Time: March 26th (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: #17 Recording: https://youtu.be/8l3MCRyviB4 Present: @mattodd @MA-Jjingyi @marijschippers Mickey Konings @wwjvdsande @MFernflower Apologies: @KlementineJBS

AGENDA AND MINUTES

@OpenSourceMycetoma/corecontrib please flag up any key issues ahead of the meeting, and please note any apologies above.

In vitro screening

[x] @MA-Jjingyi @marijschippers to report on any in vitro or in vivo screening that has taken place since the last meeting across all series. Reminder: New data to be flagged up in the Master List, until it has been incorporated into a diagram or wiki. --> @marijschippers showed the MIC50 data she generated. Approximately 50 compounds were very active. Since this is too much for a single larvae season we made a ranking. We will start with the hits from series 3 because it is a new mode of action.

Series 1 - Fenarimols

[ ] @dosreic to investigate whether it is possible to have SCYX0001294212 EPL-BS0121 and SCYX0001315839 EPL-BS0143 shipped from TCG to Wendy.

Fenarimol Paper:

Most recent file version on Dropbox remains: Fenarimol Paper January 29 V2.3 edited last Feb 27th 2024.

[x] @fantasy121 has added section on what is known of related structures inhibiting CYP51, i.e. how do our results compare to what is known of Cyp51 inhibition. @fantasy121 to add in citations to that section, then @mattodd to check it.
[x] @fantasy121 has added a new SAR diagram, also to the paper.
[x] #20

Recent Data: MYOS00510 and MYOS00518 were hits? Do any recently-tested compounds need to be incorporated in the fenarimol manuscript? e.g. Data from Sept 21?

[ ] Modelling: @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 and may report back.

Siderophores:

@wwjvdsande carried out preliminary work in this area, but the data were inconclusive, so this aspect of the project is bein paused for the moment.

Series 2 - Aminothiazoles

[ ] Schools meeting was held. #18 @KlementineJBS to update, including if any compounds in Series 2 are incoming. (Note - Whitgift visited UCL!)
[ ] All compounds have been evaluated, including from @eloizidou and @Whitgift ? Any updates to the current SAR page? Some ideas for compounds to be made next are here.
[ ] Mechanism of Action. Any clues from literature? 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

NEU-Curaxin compound library: a few compounds showed decent IC90 (e.g. MYOS00632 and the absolutely gigantic MYOS00626), see here

[X] @P-Rayner to update on which compounds are scheduled while we wait for bioassay results from first batch, see here.
[ ] @P-Rayner to update on where the students' lab notebooks are.
[ ] @marijschippers will start the in vivo work in April on 5 selected series 3 compounds from the NEU-Curaxin library

Series 5 - Benzimidazoles

Good potencies have been seen for related benzoxazoles (e.g. here.

Testing ongoing. MYOS00527 was a hit. @AndreaOtago made the latest data available Any learnings? Three of the compounds, UO17, UO22 and UO24, are eligible for in vivo screening later in the year?

Some oxazoles will be tested against Falciformispora senegalensis too (by whom?). This series will be evaluated in vivo in the new larval season <-- is this still to be done?

[ ] @AndreaOtago to update on new benzoxazoles likely to be incoming.
[ ] @dosreic suggested doing some PK 'SAR' follow up analogues so this could inform both DNDi's project and this project. @dosreic to follow up the DMPK results.
[ ] Are there any other labs with related compounds we should contact?
[ ] 3 benzoxazoles were tested in vivo, one most likely to be done this season. @MA-Jjingyi presented the data this meeting and it was decided that we need a SAR analyses on the benzoxazoles too. @AndreaOtago or @KlementineJBS would any of you be able to do that? It might be could to do that in comparison with the benzimidazoles. Since both benzimidazoles and benzoxazoles are now named series 5 might be good to differentiate them from each other by calling the benzimidazoles series 5a and the benzoxazoles series 5b in the master list. Can @AndreaOtago and @KlementineJBS do that?

Series 6: ketoximes

[ ] @dmitrij176 summarised the latest series data in a diagram - where - this issue? What has been learned from the latest data?

Commercial oxiconazole nitrate (Z isomer) is the most potent so far. Compound MYOS00419 has not been tested

[ ] @wwjvdsande to check on MYOS00419

Global Health Priority Box*

The paper is being written by @MA-Jjingyi. 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.

[ ] @mattodd to check with GSK Tres Cantos about availability of more, or analogs, since it's likely the compound originated there.

Kinase Inhibitor Library

Paper is being written by Mickey. The KCGS library was screened. Additional drugs of similar classes were sent by @bebi78 and screened by @marijschippers. In total 6 drugs from the KCGS appeared to be hits along with one from the package sent by @bebi78. <-- data?

@MA-Jjingyi previously presented larval toxicity studies results from recent compound screening. Data still need to be uploaded in spreadsheet.

Plant Extracts from Nigeria

To be re-sent to @wwjvdsande

Dundee DMPK Measurements

[ ] @mattodd to edit spreadsheet and share with MycetOS. People can then extract their own data from the sheet and incorporate. Done. Shared here. @dmitrij176 to check that all compounds shipped were evaluated. If not, we'll need to contact Lauren Webster.

AOB

[ ] Melissa Xavier (Brazil)) joined the previous meeting: @wwjvdsande has been collaborating with her on another fungal skin disease, sporotrichosis, involving a different pathogen. Proposal was to share molecules with her so as to cross-screen. This was seen as an excellent idea. Wendy will send representative samples from existing stocks.
[x] @wwjvdsande has added a column in the masterlist with regards to toxicity. We will fill in the concentration in uM at which no toxicity was noted. For most compounds that will be 20, which is the highest concentration tested. For some the concentration will be lower. I started to fill in the data @MA-Jjingyi can you fill in the rest, as well as the in vivo data which was missing? @wwjvdsande will create a wiki with the methods on how the toxicity was determined

Next Meeting

April 23rd Noon UK time (Timezones)

fantasy121 commented 8 months ago

Hi @mattodd , I have updated the Manuscript to version March 26 V2.4, and completed the three action items. It's ready for you to check.

@fantasy121 has added section on what is known of related structures inhibiting CYP51, i.e. how do our results compare to what is known of Cyp51 inhibition. @fantasy121 to add in citations to that section, then @mattodd to check it. @fantasy121 has added a new SAR diagram, also to the paper. @fantasy121 and @dmitrij176 completed all assignments to them on experimental?

KlementineJBS commented 8 months ago

I'm afraid I can't make it today as I'm away - we have little to report on the USyd end right now, but I'll have finalised our new aminothiazole targets by next month - we'll be focussing on different thioureas with pyridine rings, including dichloro rings and some isoquinolines and the like. Perhaps Erika or Peter can update on the Schools meeting instead of me?

Loved the Whitgift article by the way!

wwjvdsande commented 8 months ago

Will there be some-one from USyd, if not we should use https://ucl.zoom.us/j/99789829423

mattodd commented 8 months ago

Agreed @wwjvdsande

wwjvdsande commented 8 months ago

We started the meeting here: https://ucl.zoom.us/j/99789829423

P-Rayner commented 8 months ago

Hi all, apologies for missing this mornings meeting. For some reason the first post said 12 noon UK? Sorry for the confusion.

We don’t have lots to update at the moment. All our students are now out of the lab and are writing up. I will add to the master last all the latest compounds that I will send to @wwjvdsande after I am back from holiday. Will also include a link to elab notebooks from students. Do we have any updates on the first batch of compounds that we sent over? The students are very excited to see any results on things they have made.

Hope everyone is well and has some time off over Easter!

MFernflower commented 8 months ago

@marijschippers can you post the myos codes of the 5 series 3 compounds that are going into the larvae screen?

dmitrij176 commented 7 months ago

@wwjvdsande @MA-Jjingyi, I could not find additional potency results in the Master List for the following entry: MYOS_00150_00_01 (DM30-1). The molecule was potent at both 100 and 25 mM concentrations, but no further assessment data (IC50, IC90, in vivo) is available. Can you please check and update me on this. Thank you in advance.

MA-Jjingyi commented 7 months ago

@wwjvdsande @MA-Jjingyi, I could not find additional potency results in the Master List for the following entry: MYOS_00150_00_01 (DM30-1). The molecule was potent at both 100 and 25 mM concentrations, but no further assessment data (IC50, IC90, in vivo) is available. Can you please check and update me on this. Thank you in advance.

Hi @dmitrij176 , I checked my notebook. DM30-1 (MYOS150) was not selected to do further testing because it did not inhibit F. senegalensis strains at 100 and 25 uM. In my project, every compound was tested by both M. mycetomatis (the most common causative agent)and F. senegalensis (the second common causative agent) to narrow the number of promising candidates. then only these compounds inhibiting these two strains will be tested in vivo.

dmitrij176 commented 7 months ago

@wwjvdsande @MA-Jjingyi, I could not find additional potency results in the Master List for the following entry: MYOS_00150_00_01 (DM30-1). The molecule was potent at both 100 and 25 mM concentrations, but no further assessment data (IC50, IC90, in vivo) is available. Can you please check and update me on this. Thank you in advance.

Hi @dmitrij176 , I checked my notebook. DM30-1 (MYOS150) was not selected to do further testing because it did not inhibit F. senegalensis strains at 100 and 25 uM. In my project, every compound was tested by both M. mycetomatis (the most common causative agent)and F. senegalensis (the second common causative agent) to narrow the number of promising candidates. then only these compounds inhibiting these two strains will be tested in vivo.

Hi. But werent we originally testing all Fenarimols that showed full inhibition of M.mycetomatis at 25 mM?

MA-Jjingyi commented 7 months ago

@wwjvdsande @MA-Jjingyi, I could not find additional potency results in the Master List for the following entry: MYOS_00150_00_01 (DM30-1). The molecule was potent at both 100 and 25 mM concentrations, but no further assessment data (IC50, IC90, in vivo) is available. Can you please check and update me on this. Thank you in advance.

Hi @dmitrij176 , I checked my notebook. DM30-1 (MYOS150) was not selected to do further testing because it did not inhibit F. senegalensis strains at 100 and 25 uM. In my project, every compound was tested by both M. mycetomatis (the most common causative agent)and F. senegalensis (the second common causative agent) to narrow the number of promising candidates. then only these compounds inhibiting these two strains will be tested in vivo.

Hi. But werent we originally testing all Fenarimols that showed full inhibition of M.mycetomatis at 25 mM?

If it is necessary for you, I will check the original testing file to make sure whether the IC50 and IC90 were tested (sometimes when it did not work well, I just forgot to calculate or update IC50 and IC90). but at least this compound was not tested in vivo.

dmitrij176 commented 7 months ago

Can you check that please. I'm doing SAR scheme for my thesis and need to decide what to do with this entry. IC50 and IC90 would help if there are available. Let me know

MA-Jjingyi commented 7 months ago

Can you check that please. I'm doing SAR scheme for my thesis and need to decide what to do with this entry. IC50 and IC90 would help if there are available. Let me know

I did find the data of IC50 and IC90 and calculated them right now. IC50 is 13.6 uM and IC90 is 24.7 uM. I also upload them to the spreadsheet. please check.

dmitrij176 commented 7 months ago

Can you check that please. I'm doing SAR scheme for my thesis and need to decide what to do with this entry. IC50 and IC90 would help if there are available. Let me know

I did find the data of IC50 and IC90 and calculated them right now. IC50 is 13.6 uM and IC90 is 24.7 uM. I also upload them to the spreadsheet. please check.

Thank you Ma.

MFernflower commented 7 months ago

I was just curious if any data has come back from the first batch of compounds sent by Dr.Rayner

@wwjvdsande

On Wed, Apr 3, 2024, 9:33 AM dmitrij176 @.***> wrote:

Can you check that please. I'm doing SAR scheme for my thesis and need to decide what to do with this entry. IC50 and IC90 would help if there are available. Let me know

I did find the data of IC50 and IC90 and calculated them right now. IC50 is 13.6 uM and IC90 is 24.7 uM. I also upload them to the spreadsheet. please check.

Thank you Ma.

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wwjvdsande commented 7 months ago

@OpenSourceMycetoma/corecontrib I just added the missing data from the in vivo experiments from last year. Sorry I thought they were uploaded already. I highlighted the uploaded data in yellow

dmitrij176 commented 7 months ago

@OpenSourceMycetoma/corecontrib I just added the missing data from the in vivo experiments from last year. Sorry I thought they were uploaded already. I highlighted the uploaded data in yellow

Thank you @wwjvdsande

mattodd commented 7 months ago

Closing since everything live is being taken forward to #21

OpenSourceMycetoma / Monthly-zoom-meetings