Monthly MycetOS meeting - 23 April 2024

[wwjvdsande]

Time: April 23 (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: ErasmusMC Minute taker: USyd Previous meeting: #19 Recording of this meeting: here Present: Apologies:

AGENDA

@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. In the last meeting @marijschippers showed recent in vitro data. Compounds with a new mechanism of action were to be prioritised for the in vivo larval tests, e.g. Series 3.

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 March 26 V2.4 edited last April 23rd 2024.

• [ ] @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 has added in citations to that section. @fantasy121 has also added a new SAR diagram to the paper. Now @mattodd to check it.

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, has been in touch with @wwjvdsande and @mattodd by email, and can report back.

Series 2 - Aminothiazoles

• [ ] 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 https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/19.
• [ ] @eloizidou to complete latest LCMS/NMR characterisation of Whitgift samples. Has one sample been evaluated in vitro?
• [ ] @Whitgift have made a further sample and are planning to visit UCL June 19th.
• [ ] 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

• [ ] The NEU-Curaxin compound library: a few compounds showed decent IC90 (e.g. MYOS00632 and the absolutely gigantic MYOS00626), see https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/issues/6
• [ ] @P-Rayner to ship of his second box of student-made tricyclics to Wendy's lab and share the structures of the boxes contents on github, see https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/issues/8#issuecomment-1987265910.
• [ ] @P-Rayner to update on where the students' lab notebooks can be found. (Sources of Data Series 3 Wiki area is incomplete)
• [ ] @marijschippers to start the in vivo work in April on five selected Series 3 compounds from the NEU-Curaxin library.

Series 5 - Benzimidazoles

Good potencies have been seen for related benzoxazoles (e.g. https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325150305.

• [ ] Three benzoxazoles were tested in vivo, one most likely to be done this season. @MA-Jjingyi presented the data last meeting (#19) and it was decided that we need a SAR analyses on the benzoxazoles too. Volunteers? @AndreaOtago has made a start here.
• [ ] Should we rename the benzimidazoles series 5a and the benzoxazoles series 5b? If yes, volunteers to edit the Master List @AndreaOtago @KlementineJBS ?
• [ ] @MA-Jjingyi will write a first draft for this paper
• [ ] @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 summarised the latest series data in a diagram - https://github.com/OpenSourceMycetoma/Series-6-Ketoximes/issues/5? What has been learned from the latest data?
• [ ] The in vivo data from last season were added to the spreadsheet, @dmitrij176 to summarise.

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.

• [x] @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. Where are the data for this?

• [ ] @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 - what are next steps here? - seems like contact has been lost?!

Dundee DMPK Measurements @mattodd edited the original spreadsheet and shared with MycetOS at https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-2018038185. @dmitrij176 checked that all compounds shipped were evaluated - they were not. Update coming.

AOB

Melissa Xavier (Brazil)) joined the previous meeting: @wwjvdsande has been collaborating with her on another fungal skin disease, sporotrichosis, involving a different fungal 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 <-- done?

@wwjvdsande has added a toxicity column in the Master List. The concentration in uM at which no toxicity was noted will be added (for most compounds this is 20 uM, which is the highest concentration tested). @wwjvdsande has started this, @MA-Jjingyi to complete this, as well as the in vivo data which was missing? @wwjvdsande will create a page on the wiki with the methods on how the toxicity was determined <-- where?

Next Meeting

May 28th 8:00 UK time (Timezones)

[wwjvdsande]

I made the preliminary agenda for tomorrow. Please update if you want to add things. Remember, tomorrow is the UK noon addition, so check your calender for the correct timing! According to the agenda USyd is minute taker. Will USyd be present?

[MFernflower]

The timezone converter is not working

Can somebody please give me the time and date for Boston USA?!

@mattodd

On Mon, Apr 22, 2024, 8:50 AM Wendy van de Sande @.***> wrote:

Time: April 23 (12 noon UK) Timezones https://www.timeanddate.com/worldclock/meetingdetails.html?year=2024&month=3&day=26&hour=8&min=0&sec=0&p1=43&p2=136&p3=37&p4=771&p5=235&p6=152&p7=770&p8=250&p9=196&p10=240 .

The Outlook invite can be found #2 (comment) 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 https://teams.microsoft.com/l/meetup-join/19%3ameeting_M2I2MDcxZTgtYjZjOS00YTdmLTgwZTMtNWQ3OTc4NDY0MDNj%40thread.v2/0?context=%7b%22Tid%22%3a%22526638ba-6af3-4b0f-a532-a1a511f4ac80%22%2c%22Oid%22%3a%22a5ed84b8-5af1-42c6-9f8d-240f23a5d997%22%7d

Chair: UCL Minute taker: ErasmusMC Previous meeting: #17 https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/17 Recording: Present: @mattodd https://github.com/mattodd @MA-Jjingyi https://github.com/MA-Jjingyi @marijschippers https://github.com/marijschippers Mickey Konings @wwjvdsande https://github.com/wwjvdsande @MFernflower https://github.com/MFernflower Apologies: @KlementineJBS https://github.com/KlementineJBS

AGENDA AND MINUTES

@OpenSourceMycetoma/corecontrib https://github.com/orgs/OpenSourceMycetoma/teams/corecontrib please flag up any key issues ahead of the meeting, and please note any apologies above.

In vitro screening

@MA-Jjingyi https://github.com/MA-Jjingyi @marijschippers https://github.com/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 https://github.com/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 https://github.com/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.

@fantasy121 https://github.com/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 https://github.com/fantasy121 to add in citations to that section, then @mattodd https://github.com/mattodd to check it. @fantasy121 https://github.com/fantasy121 has added a #15 (comment) https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/15#issuecomment-1905666076, also to the paper.

20

https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/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 https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/files/12684110/26092023.MyctOS.meeting.-MA.pptx ?

Modelling: @meh-cyprian https://github.com/meh-cyprian to proceed to try to model fenarimol compounds in potential protein target (described OpenSourceMycetoma/Series-1-Fenarimols#68 (comment) 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 https://github.com/osmanwa also interested in this area and may report back. Siderophores: @wwjvdsande https://github.com/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 https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/18 @KlementineJBS https://github.com/KlementineJBS to update, including if any compounds in Series 2 are incoming. (Note - Whitgift visited UCL! https://www.ucl.ac.uk/pharmacy/news/2024/mar/whitgift-school-students-contribute-open-source-mycetoma-project-mycetos ) All compounds have been evaluated, including from @eloizidou https://github.com/eloizidou and @Whitgift https://github.com/Whitgift ? Any updates to the current SAR page https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/wiki/Overall-summary? Some ideas for compounds to be made next are OpenSourceMycetoma/Series-2-Aminothiazoles#19 https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/19. Mechanism of Action. Any clues from literature? Should we measure for synergism with itraconazole (which hits Cyp51). @dosreic https://github.com/dosreic to try to secure samples related to this paper OpenSourceMycetoma/Series-2-Aminothiazoles#11 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 OpenSourceMycetoma/Series-3-Phenothiazines#6 https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/issues/6

@P-Rayner https://github.com/P-Rayner to update on which compounds are scheduled while we wait for bioassay results from first batch, see OpenSourceMycetoma/Series-3-Phenothiazines#8 (comment) https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/issues/8#issuecomment-1987265910 . @P-Rayner https://github.com/P-Rayner to update on where the students' lab notebooks are. @marijschippers https://github.com/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. OpenSourceMycetoma/Series-1-Fenarimols#82 (comment) https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325150305 .

Testing ongoing. MYOS00527 was a hit. @AndreaOtago https://github.com/AndreaOtago #15 (comment) https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/15#issuecomment-1905575213 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 https://github.com/AndreaOtago to update on new benzoxazoles likely to be incoming.

@dosreic https://github.com/dosreic suggested doing some PK 'SAR' follow up analogues so this could inform both DNDi's project and this project. @dosreic https://github.com/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 https://github.com/MA-Jjingyi presented the data this meeting and it was decided that we need a SAR analyses on the benzoxazoles too. @AndreaOtago https://github.com/AndreaOtago or @KlementineJBS https://github.com/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 https://github.com/AndreaOtago and @KlementineJBS https://github.com/KlementineJBS do that?

Series 6: ketoximes @dmitrij176 https://github.com/dmitrij176 summarised the latest series data in a diagram - where - OpenSourceMycetoma/Series-6-Ketoximes#5 https://github.com/OpenSourceMycetoma/Series-6-Ketoximes/issues/5? 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 https://github.com/wwjvdsande to check on MYOS00419 Global Health Priority Box* The paper is being written by @MA-Jjingyi https://github.com/MA-Jjingyi.

12 (comment)

https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/12#issuecomment-1729421998.

15 (comment)

https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/15#issuecomment-1905561111 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 #15 (comment) https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/15#issuecomment-1943554945 .

@mattodd https://github.com/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 https://github.com/bebi78 and screened by @marijschippers https://github.com/marijschippers. In total 6 drugs from the KCGS appeared to be hits along with one from the package sent by @bebi78 https://github.com/bebi78. <-- data?

@MA-Jjingyi https://github.com/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 https://github.com/wwjvdsande

Dundee DMPK Measurements @mattodd https://github.com/mattodd to edit spreadsheet and share with MycetOS. People can then extract their own data from the sheet and incorporate. Done. Shared #8 (comment) https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-2018038185. @dmitrij176 https://github.com/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 https://github.com/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.

@wwjvdsande https://github.com/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 https://github.com/MA-Jjingyi can you fill in the rest, as well as the in vivo data which was missing? @wwjvdsande https://github.com/wwjvdsande will create a wiki with the methods on how the toxicity was determined

Next Meeting April 23rd Noon UK time (Timezones https://www.timeanddate.com/worldclock/meetingdetails.html?year=2024&month=4&day=23&hour=11&min=0&sec=0&p1=43&p2=136&p3=37&p4=771&p5=235&p6=152&p7=770&p8=250&p9=196&p10=240 )

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/21, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDUS5RINNKG3VKS4HZ3Y6UBSTAVCNFSM6AAAAABGSXAEFGVHI2DSMVQWIX3LMV43ASLTON2WKOZSGI2TMNBVG4ZDSOI . You are receiving this because you were mentioned.Message ID: @.***>

[bebi78]

@MFernflower Should be 7 am ET.

[KlementineJBS]

I made the preliminary agenda for tomorrow. Please update if you want to add things. Remember, tomorrow is the UK noon addition, so check your calender for the correct timing! According to the agenda USyd is minute taker. Will USyd be present?

Yes, I'll definitely be attending and can take minutes. Alice is planning to attend too.

[eloizidou]

Good morning, Apologies I will be joining the meeting late today, around 12:30, as I have another meeting before.

Regarding aminothiazoles, there are still two compounds from Whitgift school that need analysis (attached) and we can send them around end of June. Whitgift molecules.docx

Regarding possible targets for antifungal molecules from literature, tRNA synthetases, 24C-methyltransferases, 20S proteasome and maybe histone deacetylases are possibilities we can test and I believe there are commercial assay kits available. We are planning to test some of these targets over the summer with the MSc students on the aminothiazole analogues. @KlementineJBS as discussed before, we can test additional aminothiazole analogues that you have in stock, if you can send us (I estimate we will need 50-100mg).

Erika

[P-Rayner]

Hi all, just to let you know that I am teaching at 12.30 today so will only be able to be there for the first 20 mins or so. Looking forward to seeing you. Peter

[mattodd]

Not relevant to us (we're too early) but something we should keep an eye on in case we can collaborate with groups or attempt to repurpose. WHO call for data on antifungal pre-clinical R&D https://www.who.int/news-room/articles-detail/who-2024-data-call-is-now-open-for-antifungals-in-the-preclinical-development-pipeline

[mattodd]

Added page to Series 2 wiki as a placeholder for work we might want to do (as part of student projects?) to figure out the likely mechanism of action based on literature reports of aminothiazoles. Have at it! https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/wiki/Clues-to-MoA-from-Literature @eloizidou did any UCL stduents do stuff on this for their reports?

[MFernflower]

So just for the record @P-Rayner you sent one batch of tricyclics to Wendy's lab and will be sending another on soon?

@marijschippers the block of compounds sent by Dr.Rayner starts at around myos 658

On Tue, Apr 23, 2024, 8:42 AM Mat Todd @.***> wrote:

Not relevant to us (we're too early) but something we should keep an eye on in case we can collaborate with groups or attempt to repurpose. WHO call for data on antifungal pre-clinical R&D

https://www.who.int/news-room/articles-detail/who-2024-data-call-is-now-open-for-antifungals-in-the-preclinical-development-pipeline

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/21#issuecomment-2072200500, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDTCGKUUKBRYZTWOC53Y6ZJMXAVCNFSM6AAAAABGSXAEFGVHI2DSMVQWIX3LMV43OSLTON2WKQ3PNVWWK3TUHMZDANZSGIYDANJQGA . You are receiving this because you were mentioned.Message ID: @.***>

[KlementineJBS]

Minutes

Chair: ErasmusMC Minute taker: USyd Previous meeting: #19 Recording of this meeting: Present: @wwjvdsande @P-Rayner @mattodd @marijschippers @bebi78 @MFernflower @alintheopen @eloizidou @dmitrij176 , Mickey Konings Apologies: @MA-Jjingyi

Screening updates

• Marijs has performed more screening (both in vitro and in vivo) and has lots of MIC data that will be added to the masterlist by the end of the week
• compounds with new mechanism of action were prioritised for in vivo testing, e.g. Series 3
• remember that new entries will be highlighted in yellow and only un-highlighted once information has been digested into an SAR diagram or similar
• [ ] ACTION @AndreaOtago has offered to look at the data for Series 5

Series 1 - Fenarimols

• Some compounds of interest from TCG, SCYX0001294212 EPL-BS0121 and SCYX0001315839 EPL-BS0143, are no longer available. It would be good to test these in future if they become available.
• [x] ACTION @KlementineJBS will add these to the Wiki as "Desirable compounds"

Paper update

• Most recent file version on Dropbox remains: Fenarimol Paper March 26 V2.4 edited last April 23rd 2024.
• Mat has read through this draft and will re-read once more before signing off
• he will then circulate to all coauthors for a re-read before submission
• journal not yet decided - ACS Infectious Diseases will probably cover open access fees through existing agreement
• recently tested compounds will probably not be incorporated unless particularly interesting (data is currently only in vitro)

Modelling update

No one in the meeting could report on this. From agenda:

@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.

Series 2 - Aminothiazoles

• University of Sydney will be making ~20-25 compounds by the end of June, details are here and here. Focus is on the thiazole end of the molecule, trying out some dichloro combinations and fused rings.
• before publishing on this, we need to do a sweep of the literature on mechanism of action - this could be a good student project
• Wendy has a new PhD student starting who might be willing to try this, but they will need direction from the chemistry team
• [x] ACTION - create a page/post on the wiki so that we can communicate about what is required more effectively (see here)
• Erika/UCL will take over from Klementine/USyd with directing Whitgift on what targets to make next
• Peter will be sending through some more aminothiazoles soon

Not addressed directly

• [ ] 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 https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/19.
• [ ] @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

• Peter has sent through a box of some phenothiazines for testing already and will be sending another box soon
• a few of these have been tested but only at low concentrations - hopefully data becomes available soon
• Uni of York student notebooks will be made public soon
• some of the NEU/Curaxin compounds had promising activity: MYOS00632 and the absolutely gigantic MYOS00626, see here
• 4 of these NEU/Curaxin compounds screened for toxicity in vivo by @marijschippers were excellently nontoxic (which myos codes?), with minimal larvae death, while one compound showed some toxicity (which myos code?)
• toxicity screens will be repeated and then efficacy tests will follow soon after. This will be our first efficacy data for Series 3
• the compounds being screened in vivo are the Curaxin-NEU tricyclics e.g: MYOS626, 627, 628, 631, 632

Series 5 - Benzimidazoles

• Andrea is doing some SAR assessments on the benzoxazoles
• One compound was very promising in vitro and will move into toxicity screens soon, two have prolonged larval survival
• Ma is drafting these results into a paper
• Question of renaming benzimidazoles series 5a and the benzoxazoles series 5b apparently not yet decided - will need volunteers to edit masterlist

Not addressed

• [ ] @AndreaOtago to update on new benzoxazoles likely to be incoming.
• [ ] Are there any other labs with related compounds we should contact?

Series 6: ketoximes

• Dmitrij has requested that a few of the earlier compounds are tested in vivo as single isomers if there is any space in the schedule
• [ ] ACTION @dmitrij176 (and anyone else with similar concerns) to create a priority list of what would be most useful to test if possible
• Dmitrij is still working on SAR scheme and will share it later
• note that "good" survival results in vitro only result in in vivo testing if there is a significant difference between the compound and the control. selection for in vivo testing also depends on number of compounds!
• Fosravuconazole and related CYP51 inhibitors don't necessarily resolve infection in clinical settings despite having excellent preclinical results - therefore, we want to target a different enzyme (i.e not CYP51) so that we don't end up with this phenomenon being repeated

Other

Global Health Priority Box

• no particular updates other than that the paper has been submitted
• 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.
• Mat has contacted GSK to ask about analogues but not received a reply yet

Kinase Inhibitor Library

• Mickey is writing up this paper
• KCGS library was screened along with compounds of similar classes that were sent by @bebi78
• 6 hits in total
• [ ] ACTION link to data / add to masterlist
• Mickey will likely have results to share next meeting
• in vivo testing has been difficult as many compounds in this library are too toxic, will have to try lower concentrations
• [ ] ACTION @MA-Jjingyi to update spreadsheet with larval toxicity studies if not already done

Plant Extracts from Nigeria

• still not heard back from those involved
• [ ] ACTION @bebi78 will try to contact them again

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

• Melissa Xavier (Brazil) has been collaborating with Wendy on Sporothrix brasiliensis, another emergent fungal skin disease, and Wendy has agreed to share some representative samples for cross-screening
• hopefully these can be transported via a student of Melissa's

Toxicity column

• new column in masterlist gives details on toxicity
• includes concentration (uM) at which no toxicity is recorded
• for most compounds, this is 20uM (highest concentration tested)
• [ ] 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

• Bernhard has started writing about niclosamide derivatives, including some work by Ma and from the DMPK studies
• niclosamide is currently being used in diabetes and cancer clinical trials
• CURE ID in the US is collecting case reports about off-label use of existing drugs, which will be interesting to consider once they have some results
• we are looking for a pharmaceutical industry contact - someone who can attend meetings once a month and give us some advice. Ideally someone who is interested in infectious diseases, tropical diseases, phenotypic drug discovery etc
• previously the DNDI could do this - maybe we should ask @dosreic ?
• could also look towards companies e.g. there is an Indian company producing compounds similar to Series 2

Next meeting

Will be 7am for Europe/7 pm for Australia.

[KlementineJBS]

I've updated the Series 2 repo with our plans for Series 2 this year: https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/24

[MFernflower]

@lferrins seems like some promising results on the compounds you sent to Wendy's lab

[KlementineJBS]

Can someone direct me to where I can find structures/any further information on the compounds SCYX0001294212 EPL-BS0121 and SCYX0001315839 EPL-BS0143?

Also - can someone more savvy about fenarimols let me know if this page about proposed synthesis from 2018 is still active/relevant? I assume it's not up to date but don't want to delete without checking!

[P-Rayner]

So just for the record @P-Rayner you sent one batch of tricyclics to Wendy's lab and will be sending another on soon? @marijschippers the block of compounds sent by Dr.Rayner starts at around myos 658

Yes, we sent a batch back in Jan. We will have another batch to send in the coming few weeks.

[MFernflower]

@OpenSourceMycetoma/corecontrib just started work on the series 3 wiki @P-Rayner

[wwjvdsande]

@OpenSourceMycetoma/corecontrib I added the latest in vitro data. They are highlighted in yellow

[MFernflower]

For what series? @wwjvdsande

[MFernflower]

@P-Rayner is this the only ELN you students used for this years project https://tinyurl.com/YorkChemELN - or are they more that I did not document on the wiki?