title: SC83288 is a clinical development candidate for the treatment of severe malaria.
abstract: Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca2+transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pegoraro
authors.affiliation: Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Maëlle
authors.initials: M
authors.lastname: Duffey
authors.affiliation: Parasite Genomics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Thomas D
authors.identifier: 0000-0002-1246-7404
authors.initials: TD
authors.lastname: Otto
authors.affiliation: Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Rösemann
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: 4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.|Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Fehler
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lucantoni
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Don Young, Nathan Queensland 4111, Australia.
authors.forename: Vicky M
authors.identifier: 0000-0003-4914-2299
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital, F-75013 Paris, France.|AP-HP, Hôpital St Antoine, Service de Parasitologie-Mycologie, F-75012 Paris, France.
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno-Sabater
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), 91 Bd de l'hôpital, F-75013 Paris, France.|AP-HP, Groupe hospitalier La Pitié-Salpêtrière, Service de Parasitologie-Mycologie, F-75013 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, cc107, Place Eugène Bataillon, 34095 Montpellier, France.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
authors.affiliation: 4SC Discovery GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Strobl
authors.affiliation: Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Cecilia P
authors.initials: CP
authors.lastname: Sanchez
authors.affiliation: Department of Infectious Diseases, Parasitology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Center for Infection Research (DZIF), partner site Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.identifier: 0000-0002-0220-6526
authors.initials: M
authors.lastname: Lanzer
mesh_terms: D000208:Acute Disease; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D017136:Ion Transport; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D000252:Calcium-Transporting ATPases