2. Academic Validation
  3. Medicinal Chemistry Progression of Sapanisertib, the Anticancer and Dual Plasmodium Phosphatidylinositol 4-Kinase Beta and cGMP-Dependent Protein Kinase Inhibitor, for Malaria

Medicinal Chemistry Progression of Sapanisertib, the Anticancer and Dual Plasmodium Phosphatidylinositol 4-Kinase Beta and cGMP-Dependent Protein Kinase Inhibitor, for Malaria

  • J Med Chem. 2025 Jun 12;68(11):10757-10770. doi: 10.1021/acs.jmedchem.4c02799.
Samuel Gachuhi 1,  Stephanie Kamunya 1,  Stephen Fienberg 2,  Lynn Wambua 1 3,  Nicolaas Salomane 2,  Godfrey Mayoka 1,  Dale Taylor 2,  Dina Coertzen 4,  Mariette van der Watt 4,  Janette Reader 4,  Lyn-Marié Birkholtz 4 5,  Sergio Wittlin 6 7,  Liezl Krugmann 2,  Lauren B Coulson 2 3,  Kelly Chibale 1 2 3 8
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cape Town, Rondebosch ,7701 Cape Town, South Africa.
  • 2 Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa.
  • 3 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925 Cape Town, South Africa.
  • 4 Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, 0028 Pretoria, South Africa.
  • 5 Department of Biochemistry, Stellenbosch University, Matieland, Stellenbosch 7602, South Africa.
  • 6 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland.
  • 7 University of Basel, 4001 Basel, Switzerland.
  • 8 South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa.
PMID: 40377111 DOI: 10.1021/acs.jmedchem.4c02799
Abstract

We recently demonstrated that the Anticancer human mTOR Inhibitor sapanisertib displays antimalarial activity in a malaria mouse model of Infection and inhibits multiple Plasmodium kinases, including the high-value targets phosphatidylinositol 4-kinase type III beta (PI4Kβ) and cGMP-dependent protein kinase (PKG). Herein, we explore structure-activity relationships for sapanisertib analogues with benzyl and pyridyl substituents at the 7-position of the pyrazolopyrimidine core. New analogues with improved safety profiles were identified, including analogues with dual Plasmodium PI4Kβ and PKG inhibitory activity (exemplified by 19), as well as potent Plasmodium PI4Kβ inhibitors with minimal inhibitory activity against PKG (exemplified by 20). Compound 19 displayed potent antiplasmodium activity, high microsomal metabolic stability, and a good safety profile (hERG IC50 > 30; cytotoxicity selectivity index = 99). In vivo proof-of-concept, where a 4 × 50 mg kg-1 oral dose of 19 resulted in an 80% reduction in parasitemia in P. berghei-infected mice, further demonstrated the lead potential of this series.

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