Update on Malaria Libre Project Meeting - 19th April 2023

The Malaria Libre Project Meeting held on 19th April 2023 discussed key topics such as the Aryl Imidazole chemical series, potential new series, and the MMV Early Lead Criteria for the next milestone. Chemistry resources appointed by MMV were also outlined, focusing on Aryl Imidazoles as the main area of research. The meeting highlighted the importance of achieving specific criteria for the Malaria Libre project and shared insights into the current progress and challenges faced in developing effective compounds for malaria treatment.

• Malaria Libre Project
• Aryl Imidazole
• MMV Early Lead Criteria
• Chemistry Resources
• Research Progress

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1. Malaria Libre Project Meeting 19th April 2023 1

2. Agenda 1. Introduction: Malaria Libre series and next milestone (slides 3-4) 2. Aryl Imidazole as main chemical series (slides 5-11) 3. 4-Aminothienopyridines (slide 12) 4. Need for a new series? (slide 13) 2

3. Reminder: MMV Early Lead Criteria Next milestone for Malaria Libre: Early Lead delivery by Q3 2023 Main MMV criteria to be achieved 3D7 EC50 < 100 nM (asexual blood stage); no shift vs resistant strains or cross-resistance panel Cytotoxicity >100-fold; hERG IC50 > 1 M Minimum Inoculum for resistance > 106-107 parasites Aqueous solubility > 10 M (PBS); stable in plasma In vivo rodent PK: Bioavailability >20% (using stable suspension/solution in acceptable vehicle) SCID in vivo efficacy (ED90<50 mg/kg -> measure PD parameters and check consistency with MMVsola) Detailed MMV criteria can be found through the link below: https://www.mmv.org/research-development/information-scientists Need also to demonstrate potential for transition into lead optimization 3

4. Chemistry resources appointed by MMV: 3 FTEs Malaria Libre Series Transferred to A. Vaidya/M. Riscoe C. Friel s lab contribution Current main series Parked Limited work Confidential MMV1964359 Aminopyridinol 0.003, 0.007 / 4.7 0.0005 / 5.5 ~4 (Fast) pending ND MMV1804508 Cyclopropyl amide 0.19,0.07 / 2.9 pending 3.8 (Slow, lag phase) 9.7 (SI~51) 0.29 (Pb) MMV1964361 4-aminothienopyridine 0.036 / 4.9 0.018 / 5.2 ND pending ND MMV1919978 Phenyl amide 0.13, 0.35 / 4.1 0.005 / 5.5 ~4 (Fast) 8.5 (SI~70) ND (Pb: analogs active) MMV1960432 Aryl imidazole 0.045, 0.040 / 3.5 pending Compound Scaffold PfIC50 LDH (3D7,Dd2 M)/ LipE* Free potency ( M) / LipE* PRR (representative compound) ~3-4 (Moderate-Fast) Cytotoxicity (HepG2, M) Potency (liver stages, M) >25 ND DGFA/ : 0.87/>25 DGFA inactive ES gams 0.107 M ES gams 0.085 M ND (analogs inactive) Potency (transmission, M) 3.8 161 2.8 46 3.8 7.5 3.8 8.9 2.5 171 eLogD Solubility (PBS), M CACO-2 (ER; AB; BA) Microsome (h) Clint Hepatocyte (r) Clint CYP Inhibition %I @10uM hERG (K+CHO) EC50, M 27.6; 0.05; 1.43 19 56 ND (analogs inhibitors) 3.7 619; 0.01; 7.38 <3.5 13 <50% 1.4 1.6; 4.2, 6.9 33 139 <2% 10.3 1.8; 2.3, 4.3 245 92 ND ND 7.7; 0.02, 0.16 10.6 8 ND 1.6 for analog New Data *LipE = pIC50 - eLogD 4 MIR>107 for all chemotypes

5. Aryl imidazoles: Main Focus of MMV chemistry resources SAR summary Main Issues Metabolic stability, permeability and CYP issues most likely related to the di-Me imidazole core Understand shift vs. Dd2. Difficult to rationalize Include Dd2 in the test cascade along with 3D7 testing MMV1960432 Pf 3D7 IC500.045 M LogD ~3.8; MW 426; tPSA 46 Limited modifications tolerated: indole and CF3/Cl imidazoles (but higher LogD), azabenzimidazoles (some potency loss) Not tolerated: unsubstituted imidazole, NMe imidazole, 1,2,4-triazole, pyrazole hERG to be monitored, especially for imidazoles Phenyl > Pyridine > Pyrazine => SAR divergence vs. MMV portfolio compounds Indole, Benzoxazoles tolerated Cytotoxicity to be monitored, especially for compounds with LogD>3 To be further explored, appears to improve potency, shift vs Dd2 to be monitored Amenable to a variety of modifications (e.g. pyrrolidine derivatives + amide moiety => improve physchem properties and Caco-2 permeability) 5

6. Reminder: Aryl Imidazoles vs Aryl Indoles MMV1965085 3D7 IC50 0.37 M Free IC50 0.0005 M Dd2 IC50 1.27 M HepG2 5.9 M Caco-2 0 Human mics < 3.5 Rat heps 3.85 eLogD 5.12 Sol 2.5 M hERG IC50 12 M CYPs only 1A2 ~50% at 10 M Good metabolic stability despite high LogD 3D7 potency Do not meet MMV early lead criteria MMV1981184 3D7 IC50 0.52 M Free IC50 0.001 M Dd2 IC50 2.2 M HepG2 5.7 M Caco-2 0.7 Human mics 12.9 Rat heps 15.6 eLogD 5.27 Sol 2.5 M MMV1981100 3D7 IC50 0.054 M Free IC50 0.0014 M MMV1965126 3D7 IC50 0.073 M Free IC50 0.001 M Dd2 IC50 0.77 M HepG2 4.9 M Caco-2 0, PAMPA 6.7 Human mics 26.2 Rat heps 22.1 eLogD 3.59 Sol 40.7 M HepG2 6.9 M PAMPA 48.1 Human mics 58.4 Rat heps 43.6 eLogD 4.38 Sol 29.3 M similar unbound IC50s 3D7 potency Meets MMV early lead criteria Ideally we would need to achieve physchem/DMPK properties to allow testing of 1 representative of indoles and imidazoles in in vivo efficacy SCID mouse model to compare the relative in vivo MICs 6

7. Aryl Imidazoles: Targets proposed by Tony Mete based on SAR / ADME properties MMV1991768 3D7 IC50 10.17 M MMV1992247 3D7 IC50 0.98 M Albumax binding 21.91% Free IC50 0.76 M Dd2 IC50 17 M Human mics 4.84 Rat heps 2.74 eLogD 0.52 Sol >200 M MMV1991824 3D7 IC50 1.66 M ADME Tier 1 Albumax binding 53.99% Free IC50 0.76 M Human mics 9.54 Rat heps 5.32 eLogD 1.6 Sol 110 M MMV1991925 3D7 IC50 1.86 M ADME Tier 1 Albumax binding 98.26% Free IC50 0.032 M Human mics 4.09 Rat heps 3.49 eLogD 2.31 Sol 122 M Targets cancelled Substituent detrimental for activity Worth considering azabenzimidazole with pyrrolidine-piperidine substituent? Would expect low permeability Same free IC50 as for the diMe imidazole Free IC50: 1 log more potent Worth checking Dd2 and permeability MMV1794348 3D7 IC50 0.119 M R=Cl (unsuccessful synthesis attempts) R=OMe 10 mg with some formic acid Free 3D7 potency Indole > DiMe-imidazole ~ benzimidazole 7

8. Aryl Imidazoles: new data MMV1992408 3D7 IC50 0.044 M MMV1965126 3D7 IC50 0.073 M Free IC50 0.001 M Dd2 IC50 0.77 M HepG2 4.9 M Caco-2 0, PAMPA 6.7 Human mics 26.2 Rat heps 22.1 eLogD 3.59 Sol 40.7 M MMV1992409 3D7 IC50 0.607 M MMV1960332 3D7 IC50 0.164 M MMV1991996 3D7 IC50 0.088 M MMV1794346 3D7 IC50 0.122 M Albumax 52.91% Free IC50 0.053 M Worth collecting Dd2 and albumax binding ADME Tier 1 Detrimental for 3D7 potency Worth collecting Dd2 and albumax binding ADME Tier 1 Permeability to assess impact of potential intramolecular H bond Flexible amine side- chain tolerated at the top part 8

9. Aryl Imidazoles: New Data Compounds previously proposed by Iktos New data Perhaps worth considering more flexibility at this position (also for piperidine etc.) MMV1991690 3D7 IC50 1.2 M MMV1991984 3D7 IC50 1.02 M MMV1991651 3D7 IC50 0.56 M MMV1991689 3D7 IC50 2.6 M Pyridyl tolerated as benzyl replacement? MMV1992248 3D7 IC50 1.96 M MMV1992626: delivered This should allow a better understanding of the possible combinations between the top and right part of the molecule

10. Aryl Imidazoles: Latest selection of targets proposed by Iktos MMV1992279 3D7 IC50 >25 M MMV1991985 3D7 IC50 15.6 M Step 4 out of 5 unsuccessful, on-hold Initial routes (2) unsuccessful; on-hold Final compound under purification Still priority compounds in the queue (see next slide) 10

11. Aryl Imidazoles: Target Compounds currently prioritized 1st priority: Ideally NH piperidine analogues to be delivered for all of them (O-CH2-Ph-Cl as RHS for most cpds to establish if modifications tolerated) Information about costs and synthetic route for fluorinated piperidine obtained but worth prioritizing at a later stage Ongoing 8 steps Ongoing 4 steps Alternative route initiated Step 5 out of 8-9 steps 11

12. 4-Aminothienopyridines Expect issues similar to the 4-aminoquinolines (e.g hERG liability) ESAC strongly questioned the thienopyridine core due to the thiophene moiety as potential time- dependent CYP inhibitor Few analogues delivered by TCGLs to check whether the thiophene moiety can be replaced while maintaining potency against Dd2 and piperaquine-resistant strains MMV1964361 3D7 IC50 0.036 M Free IC50 0.018 M Human mics 10.6 Rat heps 8 eLogD 2.5 Sol 171 M ES gams 0.107 M MMV1991632 3D7 IC50 0.204 M ADME Tier1 Albumax binding 29.46% Free IC50 0.144 M Human mics 3.88 Rat heps 10.29 eLogD 2.02 Sol 199 M MMV1991891 3D7 IC50 0.99 M MMV1991926 3D7 IC50 1.08 M MMV1991688 3D7 IC50 0.060 M ADME Tier 1 Albumax binding 35.52% Free IC50 0.039 M Human mics 6 Rat heps 12.11 eLogD 2.02 Sol >200 M Furan analogue: similar potency but would still expect liabilities additional analogues to be exhaustive: 12

13. Need for a New Series for Malaria Libre? Risk mitigation strategy in case the arylimidazoles/indoles does not deliver TC held on the 28th of March with Natalie, Tony and Takeshi (under CDA with MMV) to evaluate remaining hits from MMV library hit generation activities Interest expressed around a few series Additional hit validation/profiling required and need for internal prioritization at MMV before giving a new series to Malaria Libre 13