Malaria is a global infectious disease with devastating human impact. The high prevalence of resistance towards existing drugs necessitates development of new drug therapies. De novo pyrimidine biosynthesis is an essential and non-redundant pathway in the malarial parasite, but not in mammals, and the fourth enzyme in this pathway, dihydroorotate dehydrogenase (DHODH), offers host-parasite differences at its active site. A high-throughput screen of a small-molecule library identified a number of good inhibitors of malarial DHODH. The most promising hit, GR34, is a potent and selective inhibitor of Plasmodium falciparum DHODH (IC50 = 38 nM) and demonstrates similar potent activity against parasites in whole cell assays, while having no effect on a cultured mammalian cell line. The molecule is synthesized at low cost in 3 steps. Preliminary pharmacokinetic studies have demonstrated that GR34 is orally bioavailable in rats and metabolic studies confirm that the GR34 scaffold should be pharmaceutically acceptable. The compound is well tolerated in both mice and rats with no current evidence of limiting toxicity. The next goal is to design and deliver a clinical development candidate with improved inhibitory activity against DHODH. The initial focus will be to optimize the GR34 lead compound with respect to its in vivo biological activity profile and pharmaceutical developmental properties (ADME, toxicity). A combination of structural biology and medicinal chemistry will help determine which parts of the lead molecule can be improved without loosing desirable properties. We will also prioritize DHODH inhibitors based on lack of cross-resistance with existing drugs, and with low propensity to acquire drug resistance de novo. The project will also advance a backup candidate from the lead development series and explore other chemically attractive alternative scaffolds derived from the initial HTS. The proposed work plan encompasses an integrated and multi-disciplinary approach, bringing together the expertise of the three laboratories: Biochemistry and structural biology will be performed at the University of Texas Southwestern Medical Center (Phillips lab); Medicinal chemistry and malaria biology will be performed at the University of Washington in Seattle (Rathod lab); and ADME lead optimization and preclinical development progression will be performed at Monash University (Charman lab). MMV has a well-established target product profile for drug development candidates for malaria, and these criteria will inform the work plan to develop DHODH inhibitors as novel anti-malarials. Once a compound has been nominated, MMV will fund and manage the GLP preclinical development program and First in Human (FIH) Phase 1 clinical trials as part of its internally funded clinical development program. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI075594-02
Application #
7487818
Study Section
Special Emphasis Panel (ZAI1-TP-M (M1))
Program Officer
Rogers, Martin J
Project Start
2007-09-01
Project End
2012-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$1,069,709
Indirect Cost
Name
Medicines for Malaria Venture
Department
Type
DUNS #
480918742
City
Geneva
State
Country
Switzerland
Zip Code
1215
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Deng, Xiaoyi; Matthews, David; Rathod, Pradipsinh K et al. (2015) The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions. Acta Crystallogr F Struct Biol Commun 71:553-9
Phillips, Margaret A; Lotharius, Julie; Marsh, Kennan et al. (2015) A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci Transl Med 7:296ra111
Deng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah et al. (2014) Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J Med Chem 57:5381-94
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Coteron, Jose M; Marco, Maria; Esquivias, Jorge et al. (2011) Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential. J Med Chem 54:5540-61
Gujjar, Ramesh; El Mazouni, Farah; White, Karen L et al. (2011) Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. J Med Chem 54:3935-49
Ganesan, Suresh M; Morrisey, Joanne M; Ke, Hangjun et al. (2011) Yeast dihydroorotate dehydrogenase as a new selectable marker for Plasmodium falciparum transfection. Mol Biochem Parasitol 177:29-34

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