2. Academic Validation
  3. UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria

  • Antimicrob Agents Chemother. 2018 Aug 27;62(9):e00012-18. doi: 10.1128/AAC.00012-18.
Christel Brunschwig 1,  Nina Lawrence 1,  Dale Taylor 1,  Efrem Abay 1,  Mathew Njoroge 1,  Gregory S Basarab 1,  Claire Le Manach 2,  Tanya Paquet 2,  Diego Gonzàlez Cabrera 2,  Aloysius T Nchinda 2,  Carmen de Kock 1,  Lubbe Wiesner 3,  Paolo Denti 3,  David Waterson 4,  Benjamin Blasco 4,  Didier Leroy 4,  Michael J Witty 4,  Cristina Donini 4,  James Duffy 4,  Sergio Wittlin 5 6,  Karen L White 7,  Susan A Charman 7,  Maria Belén Jiménez-Díaz 8,  Iñigo Angulo-Barturen 8,  Esperanza Herreros 8,  Francisco Javier Gamo 8,  Rosemary Rochford 9,  Dalu Mancama 10,  Theresa L Coetzer 11,  Mariëtte E van der Watt 12,  Janette Reader 12,  Lyn-Marie Birkholtz 12,  Kennan C Marsh 13,  Suresh M Solapure 14,  John E Burke 15,  Jacob A McPhail 15,  Manu Vanaerschot 16,  David A Fidock 16 17,  Paul V Fish 18,  Peter Siegl 19,  Dennis A Smith 20,  Grennady Wirjanata 21,  Rintis Noviyanti 22,  Ric N Price 21 23,  Jutta Marfurt 21,  Kigbafori D Silue 24,  Leslie J Street 2,  Kelly Chibale 25 26 27
Affiliations

Affiliations

  • 1 Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa.
  • 2 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
  • 3 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa.
  • 4 Medicines for Malaria Venture, Geneva, Switzerland.
  • 5 Swiss Tropical and Public Health Institute, Basel, Switzerland.
  • 6 University of Basel, Basel, Switzerland.
  • 7 Centre for Drug Candidate Optimisation, Monash University, Melbourne, Victoria, Australia.
  • 8 GlaxoSmithKline, Tres Cantos Medicines Development Campus, Madrid, Spain.
  • 9 Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, USA.
  • 10 Biosciences, Council for Scientific and Industrial Research, Pretoria, South Africa.
  • 11 Plasmodium Molecular Research Unit, Wits Research Institute for Malaria, Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa.
  • 12 Department of Biochemistry, Institute for Sustainable Malaria Control and South African Medical Research Council Collaborating Centre for Malaria Research, University of Pretoria, Pretoria, South Africa.
  • 13 AbbVie, North Chicago, Illinois, USA.
  • 14 Nagarjuna Gardens, Bangalore, India.
  • 15 Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
  • 16 Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA.
  • 17 Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
  • 18 Alzheimer's Research UK UCL Drug Discovery Institute, Faculty of Brain Sciences, University College London, London, United Kingdom.
  • 19 Siegl Pharma Consulting LLC, Blue Bell, Pennsylvania, USA.
  • 20 Independent Researcher, Walmer, Kent, United Kingdom.
  • 21 Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia.
  • 22 Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
  • 23 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
  • 24 Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire.
  • 25 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, South Africa kelly.chibale@uct.ac.za.
  • 26 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.
  • 27 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
PMID: 29941635 DOI: 10.1128/AAC.00012-18
Abstract

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the Parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K Inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

Keywords

1-phosphatidylinositol 4-kinase inhibitor; Plasmodium spp.; absorption; distribution metabolism; drug discovery; excretion; human dose prediction; in vivo efficacy; malaria; pharmacokinetic/pharmacodynamic modeling; pharmacokinetics.

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