Malaria Libre open project meeting

The Malaria Libre Open Project Meeting scheduled for 25/01/2024 will feature updates from key project members including Dr. Diego Gonzalez Cabrera and Dr. Didier Leroy. The meeting will cover an introduction to Malaria Libre, project updates, and allow for any other business discussions. The project team is open to anyone interested in proposing new targets for medicinal chemistry and assays. The meeting will provide insight into MMV-supported projects and data from 20,000 hits in ChEMBL.

• Malaria Libre
• Project Meeting
• Update
• Medicinal Chemistry
• Assays

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1. Malaria Libre open project meeting 25/01/2024 Diego Gonzalez Cabrera & Didier Leroy

2. Agenda 25/01/2024 UTC 12.00 pm - 1.00 pm Date (DD/MM/YY) GMT 12.00 pm - 1.00 pm IST 17:30 pm - 18:30 pm Location Time Project name Attendees Malaria Libre Darren Creek (DC) Takeshi Yura (TY) Natalie Hawryluk (NH) Antonio Mete (AM) Jeremy Burrows (JB) Didier Leroy (DL) Anna Aguiar (AA) Diego Gonzalez Cabrera (DGC) Sanjay Batra (SB) Kishor Mohanan (KM) Clinton Veale (CV) Carolyn Friel (CF) Chase Smith (CS) Isaac Attah (IA) Saman Habib (SH) Niti Kumar (NK) Shailja Jnu (SJ) Andre Godoy (AG) Caroline Aguiar (CA) Akhil Vaidya (AV) Martine Keenan (MK) Vinicius Barros (VB) Christopher Housseman (CH) Abhijit Kundu (AK) Atanu Ghoshal (AG) Anna Quattropani (AQ) Benoit Laleu (BL) Shailja Singh (SS) 1. Introduction to Malaria Libre - DL (15 min) 2. Malaria Libre Project Update - DGC (40 min) 3. AOB - All (5 min) 2

3. Project team Open to anybody interested and motivated to propose new targets for medicinal chemistry and/or assays Current core team members: PI and Med. Chem: Dr Diego Gonzalez Cabrera Med. Chem. Expert Advisors: Drs Natalie Hawryluk and Antonio Mete Chemistry TCGLS CRO: Drs Abhijit Kundu and Atanu Ghoshal Support Compound & Data Management: Mrs Anna Adam MMV Project Director: Dr Didier Leroy MMV Guidance for Med. Chemistry: Dr Jeremy Burrows Past core team members: Dr Beno t Laleu: MMV project director till Nov. 2023 Dr Takeshi Yura: ESAC mentor till end of 2023 3

4. MMV-supported projects Malaria Libre project is currently in H2L 4

5. Data from the 20,000 hits in ChEMBL The full list of the 20,000 hits from Plasmodium falciparum whole cell screening originates from the GlaxoSmithKline Tres Cantos Antimalarial Set (TCAMS), Novartis-GNF Malaria Box Data set and St. Jude Children's Research Hospital s Dataset are available on the ChEMBL website. Index 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ChEMBL_NTD_ID GNF-Pf-2381 GNF-Pf-996 TCMDC-124312 TCMDC-124192 GNF-Pf-1569 GNF-Pf-4824 TCMDC-124474 GNF-Pf-60 GNF-Pf-2750 GNF-Pf-4461 GNF-Pf-3473 TCMDC-125125 TCMDC-124241 TCMDC-125583 SJ000039582 Source GNF GNF GSK GSK GNF GNF GSK GNF GNF GNF GNF GSK GSK GSK StJude Activity (EC50 uM) 1.372 0.855 COC(=O)c1ccc(cc1)C(=O)Nc2ccc(cc2)c3nc4cc(NC(=O)c5ccc(cc5)C(=O)OC)ccc4[nH]3 0.565598476 COc1ccc(cc1)N2CCN(CC2)C(CNC(=O)C3CCCCC3)c4ccc5OCOc5c4 0.639573215 CCCCOC(=O)c1ccc(Nc2cc(C)nc3ccc(OC)cc23)cc1 0.86 Nc1c(nnn1Cc2ccc(F)cc2Cl)C(=O)NCc3ccccc3 0.554 CCCc1cc(O)c2C3=C(CN(C)CC3)C(=O)Oc2c1 0.330441791 COc1ccc(CNC(=O)C2=CC3=C(N=C4C=CC=CN4C3=O)N(CCc5ccccc5)C2=N)cc1 1.25 Cc1cccc(OCC(O)CN2CCN(CC(=O)c3ccc(Br)cc3)CC2)c1 0.589 COC(=O)C1=C(C)N(CC=C)C(=O)/C/1=C\c2ccccc2 0.907 O=C(N1CCN(Cc2ccccc2)CC1)c3ccc4nc(sc4c3)N5CCCCC5 1.507 CCCc1c(C)nc2ccc(Br)cc2c1O 0.79193223 COc1ccc(cc1)c2cn3c(C(=O)Nc4ccccc4Cl)c(c5CCCCn2c35)c6ccccc6 0.868968102 Cc1ccc(cc1)N2C(=O)C3C(C2=O)C4(C(=O)C3(C(=C4c5ccccc5)c6ccccc6)c7ccccc7)c8ccccc8 1.026892859 CC1=CC(=O)Oc2c1ccc3oc(C(=O)c4ccc(C)cc4)c(C)c23 1.4635 CN(C)c1ccc(Nc2c3ccccc3nc4ccccc24)cc1 Canonical_Smiles BATCH_NO STK699776 BAS 00255260 G856-4237 AG-205/10703018 STL094644 OSSL_050662 OSSK_492696 BAS 00226272 4031-1806 C858-0860 BAS 00333897 STK572179 5376856 STK617620 09/01/20 CCOc1ccc(CN2CCN(CC(O)COc3ccc(OCC(O)CN4CCN(Cc5ccc(OCC)cc5)CC4)cc3)CC2)cc1 Feel free to dive into the database and select scaffolds that look attractive to your chemist eyes! 5

6. Imidazole and Derivatives MMV1960432 MMV1981100 MMV1992700 0.046/ 0.041 0.054/ 0.67 3D7/ Dd2 IC50( M) Free 3D7 IC50( M) Cytotox HepG2 CC50( M)/ SI Solubility PBS pH 7.4 ( M) 0.001 - 7/ 130 - 161 29 - 19 58 - HLM CLint, app( L/min/mg) Rat Hep CLint, app( L/min/106cells) Exp. LogD7.4 hERG IC50( M) 56 44 - 3.8 4.4 - 3.7 - - 197 Compounds have been synthesized - mostly dimethyl imidazole 6

7. Compounds of Interest Issues to address: Cross-resistance Metabolic stability Low cell permeability hERG liability? Early Criteria 0.1 0.1 >100-fold 10 11.6 10 MMV2214218 0.052/ - 0.022 - 181 100 20 MMV1991359 0.078/ 0.14 0.02 4/ 51 6 16 47 MMV1818856 0.24/ 0.29 0.11 15/ 63 15 70 41 8 3 3 3D7/ Dd2 IC50( M) Free 3D7 IC50( M) Cytotox HepG2 CC50( M)/ SI Solubility PBS pH 7.4 ( M) HLM CLint, app( L/min/mg) Rat Hep CLint, app( L/min/106cells) Caco-2 Permeability Papp A > B (10-6cm/s) Exp. LogD7.4 >2 - - 1-3 3.2 4.2 7

8. Cross-Resistance Compounds with predicted pKa 9.5 (most basic center) show cross-resistance (Dd2/3D7 4-fold) Dd2/3D7 ratio (Cross-Resistance) The pKaof the most basic centre of specific compounds should be measured To confirm observed trend - pKa 9.5 -> cross-resistance To determine the range of pKaneeded for antimalarial activity Cross-resistance has been confirmed in K1, NF54 and RF12 for MMV1804317, MMV1960332 and MMV1965126 @ STPH <3-fold Predicted pKaof most basic centre 8

9. Metabolic Stability In general, imidazole and its derivatives show high to moderate metabolically instability in microsomes and hepatocytes Human Liver Microsomes CLint, app ( L/min/mg) Rat Hepatocytes CLint, app ( L/min/106cells) Analogues with exp. LogD7.4<3 are more metabolically stable than compounds with LogD7.4>3 Early Lead Criteria HLM CLint, app 11.6 L/min/mg Early Lead Criteria Rat Hep CLint, app 10 L/min/106cells Experimental LogD7.4 9

10. Permeability Caco-2 vs PAMPA Paracellular/ Active Uptake Caco-2 Papp (10-6cm/s @ pH 7.4) Caco-2 Papp (10-6cm/s @ pH 7.4) Active Efflux PAMPA Papp (10-6cm/s) Experimental LogD7.4 Initial data suggests involvement of active efflux -> Caco-2 assay of choice Caco-2 permeability observed at LogD <4 10

11. Conclusions Series Stopped due to number of issues Cross-resistance Low metabolic stability and permeability and potential hERG liability 11

12. Indole and Derivatives MMV1991824 MMV1991925 MMV2213854 MMV2213853 MMV2213616 MMV2213184 1.7/ - 1.9/ - 1.7/ - 0.34/ 3.9 0.43/ 4.4 0.25/ 2 3D7/ Dd2 IC50( M) 0.78 0.03 0.13 Free 3D7 IC50( M) 4/ 12 9/ 21 16/ 64 Cytotox HepG2 CC50( M)/ SI 110 122 Requested Requested 192 Solubility PBS pH 7.4 ( M) 10 4 4 7 13 HLM CLint, app( L/min/mg) 5 3 <1.2 <1.2 <1.2 Rat Hep CLint, app( L/min/106cells) 1.6 2.3 Requested Requested 1.5 Exp. LogD7.4 - - - Requested Requested - hERG IC50( M) 83 Compounds have been synthesized MMV2213853, MMV2213616 and MMV2213184 cores show a combination of moderate anti-plasmodium potency and good ADMET properties

13. CYP Inhibition MMV2213853 MMV2213616 MMV2213184 0.34/ 3.9 0.43/ 4.4 0.25/ 2 3D7/ Dd2 IC50( M) 22/ 77 28/ 63 23/ 69 CYP1A2 % Inhib. @ 1/ 10 M 2/ 14 9/ 20 7/ 15 CYP2C19 % Inhib. @ 1/ 10 M 1/ 9 13/ 23 6/ 12 CYP2C9 % Inhib. @ 1/ 10 M 91/ 98 37/ 79 14/ 37 CYP2D6 % Inhib. @ 1/ 10 M 13/ 60 79/ 96 13/ 29 CYP3A4 % Inhib. @ 1/ 10 M MMV2213184 core shows lower CYP inhibition and has been prioritized 13

14. Compounds of Interest Issues to address: Cross-resistance Low cell permeability hERG liability? Early Criteria 0.1 MMV1992698 MMV2214591 MMV2214719 0.72/ 2.2 0.022/ 0.073 0.015/ 0.019 3D7/ Dd2 IC50( M) Free 3D7 IC50( M) Cytotox HepG2 CC50( M)/ SI Solubility PBS pH 7.4 ( M) 0.004 0.004 0.001 0.1 >100-fold - 4/ 182 5/ 333 77 76 129 10 6 11 48 HLM CLint, app( L/min/mg) Rat Hep CLint, app( L/min/106cells) Caco-2 Permeability Papp A > B (10-6cm/s) Exp. LogD7.4 hERG ( M) 11.6 7 2 20 10 Could not be Measured 3.3 >2 - - 1-3 3.1 4.1 >10 - Requested Requested 14

15. MMV1992698 Rat PK Study 0.72/ 2.2 3D7/ Dd2 IC50( M) Solubility PBS pH 7.4 ( M) Hepatocyte CLint, apprat (mL/min/kg) CLbrat (mL/min/kg) Rat Plasma Binding (%) 77 33 MMV1992698 5.6 99.9 100.000 In vivo CLu(mL/min/kg) PAMPA Permeability Papp A > B (10-6cm/s) 5600 10.000 0.04 Concentration ( M) PK Rat 1.000 Route i.v. p.o. 3 mg/kg IV Nominal dose (mg/kg) 3 5 0.100 5 mg/kg PO Cmax( M) - 0.35 Tmax(h) - 5.3 0.010 t1/2terminal (h) 5.7 - Rat CLb(mL/min/kg) 5.6 - 0.001 Vss(L/kg) 1.8 - 0 4 8 12 16 20 24 F (%) - 14 Time (h) 15

16. Cross-Resistance Data suggest most compounds with experimental LogD7.4<3 show cross-resistance Dd2/3D7 ratio (Cross-Resistance) -OCF3substituent seems to decrease Dd2/ 3D7 ratio <3-fold Experimental LogD7.4 16

17. Caco-2 Permeability Caco-2 Papp (10-6cm/s @ pH 7.4) Experimental LogD7.4 Initial data suggests that indole and derivatives show poor cell permeability Focus on reducing ionization and desolvation to increase permeability 17

18. Latest Data MMV2214718 MMV2214670 MMV2240071 MMV2213615 MMV2214310 MMV2240070 0.092/0.24 0.48/ 1.1 0.34/ 5.4 0.16/ 0.67 0.22/0.59 11/ 21 3D7/Dd2 IC50( M) HepG2 CC50( M) Sol. PBSpH7.4( M) - - 76 - 4 - HLM CLint, app( L/min/mg) 16 - Rat Hep CLint, app( L/min/106cells) MMV2214591 MMV2240167 MMV2240069 MMV2240168 MMV2240333 MMV2227029 0.022/ 0.073 0.055/ 0.9 0.29/ 2.2 3D7/Dd2 IC50( M) HepG2 CC50( M) Sol. PBSpH7.4( M) 4/ 182 76 11 HLM CLint, app( L/min/mg) 18 Rat Hep CLint, app( L/min/106cells) 2

19. Latest Data MMV2214591 MMV2240067 MMV2240334 MMV2240335 MMV2240336 MMV2240332 0.022/ 0.073 0.03/ 0.22 3D7/Dd2 IC50( M) HepG2 CC50( M) Sol. PBSpH7.4( M) 4/ 182 76 11 HLM CLint, app( L/min/mg) 2 Rat Hep CLint, app( L/min/106cells) MMV2240068 MMV2213184 MMV2240169 0.032/ 0.27 0.25/ 2 3D7/Dd2 IC50( M) HepG2 CC50( M) Sol. PBSpH7.4( M) 16/ 64 192 13 HLM CLint, app( L/min/mg) 19 <1.2 Rat Hep CLint, app( L/min/106cells)

20. Summary Compounds show high antiplasmodium activity, metabolic stability and aqueous solubility (e.g., MMV2214591) Expand SAR with MMV2213184 core Cell permeability is the main issue to solve Reduce ionization and/or desolvation to increase permeability 20

21. Proposed Targets - Bin 1 44 40 53 42 51 44 TPSA 3.8 3.4 3.1 3 3.3 3.1 Calc. LogD 1 2 2 1 1 1 HBD 8.5 8.5 8.9 9 8.9 8.6 Calc. pKa TM222 50 50 44 63 66 TPSA 2.7 2.7 3.5 3.5 2.7 Calc. LogD 2 2 1 1 2 HBD 9.1 9.2 9.2 6.2 8.9 Calc. pKa 21

22. Thienopyridine and Derivatives MMV1964361 MMV2214720 MMV1991632 MMV1991688 MMV2064342 MMV1991891 MMV2214173 MMV2213965 0.036/ 12/ 15 0.2/ 3 0.061/ 0.32 0.32/ 10 1.1/ 6 4.9/ 0.21/ 3D7/ Dd2 IC50( M) 0.018 - 0.14 0.039 Requested - - Requested Free 3D7 IC50( M) Cytotox HepG2 CC50( M)/ SI Solubility PBS pH 7.4 ( M) HLM CLint, app ( L/min/mg) Rat Hep CLint, app ( L/min/106cells) Requested 17/ 1 Requested Requested - - Requested 171 - 200 200 Requested - - Requested 12 - 4 6 4 - - 22 9 - 10 12 34 - - 34 2.5 - 0.5 2 Requested - - Requested Exp. LogD7.4 To be Requested To be Requested To be Requested To be Requested - - - - hERG IC50( M) 22

23. Compounds of Interest Issues to address: Low activity Cross-resistance Cytotoxicity Low cell permeability? hERG liability? Early Criteria 0.1 MMV2214083 MMV2214084 MMV2240017 0.032/ 0.048/ 0.013/ 0.076 3D7/ Dd2 IC50( M) Free 3D7 IC50( M) Cytotox HepG2 CC50( M)/ SI Solubility PBS pH 7.4 ( M) HLM CLint, app( L/min/mg) Rat Hep CLint, app( L/min/106cells) Caco-2 Permeability Papp A > B (10-6 cm/s) 0.004 0.1 >100-fold Requested Requested Requested Requested Requested Requested 10 Requested Requested Requested 11.6 Requested Requested Requested 10 >2 Requested Requested Requested 1-3 Requested Requested Requested Exp. LogD7.4 23

24. Latest Data MMV1964361 0.036 MMV2240170 MMV2239964 >25/ >25 MMV2240016 19.2 MMV2239963 2.6/ 2.4 3D7/Dd2 IC50( M) HepG2 CC50( M) Sol. PBSpH7.4( M) Requested 14/ - 1/ - 19/ 7 171 - - 12 - - HLM Clint, app( L/min/mg) 9 - - Rat Hep CLint, app( L/min/106cells) MMV2239983 0.15/ MMV2240017 0.013/ 0.076 3D7/Dd2 IC50( M) HepG2 CC50( M) Sol. PBSpH7.4( M) 12/ 80 6/ 462 HLM CLint, app( L/min/mg) 24 Rat Hep CLint, app( L/min/106cells)

25. Latest Data MMV2213965 MMV2214562 MMV2214561 MMV2214666 MMV2214667 MMV2234098 0.65/ 3.7 0.17/ 0.39 0.16/ 0.34 0.16/ 0.24 >10/ >10 21/ 22 3D7/Dd2 IC50( M) 10/ 15 5/ 31 4/ 25 - - HepG2 CC50( M) 127 - - Sol. PBSpH7.4( M) 22 12 4 - - HLM CLint, app( L/min/mg) 34 4 2 - - Rat Hep CLint, app( L/min/106cells) 25

26. Proposed Targets - Bin 1 37 42 25 64 37 41 54 TPSA 2 2.2 2.2 1.3 1.9 2.7 2.4 Calc. LogD 2 1 1 2 2 1 1 HBD MMV1964361 core is viewed as problematic, however, it is the easiest to synthesize It was decided to synthesize furopyridine or oxazolopyridine compounds with the best substituents of thienopyrine series 26

27. Timelines and Goals Q1 2023 Q2 2023 Q3 2023 Q4 2023 Q1 2024 Q2 2024 Q3 2024 Q4 2024 Q1 2025 Q2 2025 Q3 2025 Q4 2025 Improve Activity and Permeability of Indole Series Frontrunner(s) Profiling Imidazole Series Stopped H2L Studies on Indole Series Pf NSG Study PK/PD Model Rat PK Studies Parasite Lifecyle Fingerprinting Resistance Risk Assessment 2oPharmacology Improve Activity and Permeability, reduce Cross- resistance and Cytotoxicity of Thienopyridine Series Frontrunner(s) Profiling H2L Studies on Indole Series Pf NSG Study PK/PD Model Identify series, meeting the MMV Validated Hit criteria suitable for Hit-to-Early Lead studies End Q2 2024 identify Frontrunner(s) and end of Q4 2024 complete Early Lead profiling of Indole Series 27