H3D is Africa’s first integrated drug discovery and development centre with the mission to discover innovative life-saving medicines for the African patient population. H3D has drug discovery programs focused on the development of pre-clinical candidates for malaria, tuberculosis (TB) and antimicrobial resistance. Research platforms include medicinal chemistry, ADME (Absorption, Distribution, Metabolism, Excretion)/DMPK (drug metabolism and pharmacokinetics) and TB and malaria biology for phenotypic screening. More recently, H3D has started expanding their efforts to incorporate target-based drug discovery approaches, including platforms for recombinant protein production, target-based screening and structural biology.
Plasmodium kinase platform for target-based malaria drug discovery
To combat drug resistance and eradicate malaria, new drugs with novel modes of action that are effective against multiple stages of the parasite life-cycle are urgently required. The success of human kinase inhibitors for the treatment of cancer, coupled with the elucidation of the kinome of many parasitic pathogens, has led to a new and growing interest in targeting kinases for the treatment of parasitic diseases.
Plasmodium kinases essential to both asexual blood stages of the parasite life-cycle as well as the sexual stages responsible for transmission of infection have been identified and are being explored as drug targets for the treatment of malaria. The most advanced Plasmodium kinase inhibitor, MMV390048 currently in Phase IIa clinical trials for the treatment of malaria, was discovered by an international team led by the University of Cape Town (UCT) Drug Discovery and Development Centre (H3D) in partnership with Medicines for Malaria Venture (MMV). This compound as well as other related preclinical candidates, which were developed from phenotypic whole-cell screening hits, potently inhibit Plasmodium falciparum phosphatidylinositol 4-kinase (PfPI4K) displaying minimal off-target activity against human kinases.
kinase and the aurora-related protein kinases, to enable inhibitor screening and structural biology studies to guide medicinal chemistry programs. In vitro biochemical functional assays and high-resolution structure determination of protein targets can provide powerful information to drive structure-based drug discovery programs and direct the optimisation of hit compounds for both potency against a valued target and selectivity relative to off-targets. In collaboration with START, we are establishing the enzymology and structural biology components of a Plasmodium kinase platform, with focus on PI4K, cGMP-dependent protein kinase and the aurora-related protein kinases, to enable inhibitor screening and structural biology studies to guide medicinal chemistry programs.
- Brunschwig, C.; Lawrence, N.; Taylor, D.; Abay, E.; Njoroge, M.; Basarab, G. S.; Le Manach, C.; Paquet, T.; Cabrera, D. G.; Nchinda, A. T.; de Kock, C.; Wiesner, L.; Denti, P.; Waterson, D.; Blasco, B.; Leroy, D.; Witty, M. J.; Donini, C.; Duffy, J.; Wittlin, S.; White, K. L.; Charman, S. A.; Jimenez-Diaz, M. B.; Angulo-Barturen, I.; Herreros, E.; Gamo, F. J.; Rochford, R.; Mancama, D.; Coetzer, T. L.; van der Watt, M. E.; Reader, J.; Birkholtz, L. M.; Marsh, K. C.; Solapure, S. M.; Burke, J. E.; McPhail, J. A.; Vanaerschot, M.; Fidock, D. A.; Fish, P. V.; Siegl, P.; Smith, D. A.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Silue, K. D.; Street, L. J.; Chibale, K. UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob. Agents Chemother. 2018, 62, 10.1128/AAC.00012-18.
- Kandepedu, N.; Gonzàlez Cabrera, D.; Eedubilli, S.; Taylor, D.; Brunschwig, C.; Gibhard, L.; Njoroge, M.; Lawrence, N.; Paquet, T.; Eyermann, C. J.; Spangenberg, T.; Basarab, G.S.; Street, L.J.; Chibale, K. Identification, Characterization, and Optimization of 2, 8-Disubstituted-1, 5-naphthyridines as Novel Plasmodium falciparum Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria. J. Med. Chem. 2018, 61, 5692-5703.
- Cabrera, D. G.; Horatscheck, A.; Wilson, C. R.; Basarab, G.; Eyermann, C. J.; Chibale, K. Plasmodial kinase inhibitors: license to cure? J. Med. Chem. 2018, 61, 8061-8077.
- Paquet, T.; Le Manach, C.; Cabrera, D. G.; Younis, Y.; Henrich, P. P.; Abraham, T. S.; Lee, M. C. S.; Basak, R.; Ghidelli-Disse, S.; Lafuente-Monasterio, M. J.; Bantscheff, M.; Ruecker, A.; Blagborough, A. M.; Zakutansky, S. E.; Zeeman, A. M.; White, K. L.; Shackleford, D. M.; Mannila, J.; Morizzi, J.; Scheurer, C.; Angulo-Barturen, I.; Martinez, M. S.; Ferrer, S.; Sanz, L. M.; Gamo, F. J.; Reader, J.; Botha, M.; Dechering, K. J.; Sauerwein, R. W.; Tungtaeng, A.; Vanachayangkul, P.; Lim, C. S.; Burrows, J.; Witty, M. J.; Marsh, K. C.; Bodenreider, C.; Rochford, R.; Solapure, S. M.; Jimenez-Diaz, M. B.; Wittlin, S.; Charman, S. A.; Donini, C.; Campo, B.; Birkholtz, L. M.; Hanson, K. K.; Drewes, G.; Kocken, C. H. M.; Delves, M. J.; Leroy, D.; Fidock, D. A.; Waterson, D.; Street, L. J.; Chibale, K. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci. Transl. Med. 2017, 9, 10.1126/scitranslmed.aad9735.