Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria

Christel Brunschwig, Nina Lawrence, Dale Taylor, Efrem Abay, Mathew Njoroge, Gregory S. Basarab, Claire Le Manach, Tanya Paquet, Diego Gonzàlez Cabrera, Aloysius T. Nchinda, Carmen De Kock, Lubbe Wiesner, Paolo Denti, David Waterson, Benjamin Blasco, Didier Leroy, Michael J. Witty, Cristina Donini, James Duffy, Sergio Wittlin & 28 others Karen L. White, Susan A. Charman, Maria Belen Jimenez-Diaz, Iñigo Angulo-Barturen, Esperanza Herreros, Francisco Javier Gamo, Rosemary Rochford, Dalu Mancama, Theresa L. Coetzer, Mariëtte E. Van der Watt, Janette Reader, Lyn Marie Birkholtz, Kennan C. Marsh, Suresh M. Solapure, John E. Burke, Jacob A. McPhail, Manu Vanaerschot, David A. Fidock, Paul V. Fish, Peter Siegl, Dennis A. Smith, Grennady Wirjanata, Rintis Noviyanti, Ric N. Price, Jutta Marfurt, Kigbafori D. Silue, Leslie J. Street, Kelly Chibaleb

Research output: Contribution to journalArticleResearchpeer-review

13 Downloads (Pure)

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-2Rnull 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.

We acknowledge the following: Nesia Barnes and Warren Olifant from H3D, University of Cape Town (South Africa), for the ADME assays; Virgil Verhoog and Sumaya Salie from H3D, University of Cape Town (South Africa), for the P. falciparum blood stage assays; Trevor Finch from the Division of Pharmacology, University of Cape Town (South Africa), for assistance with the animal work; Michael Delves, Andrea Ruecker, and Robert E. Sinden from the Cell and Molecular Biology laboratory, Imperial College, London (United Kingdom), for the gamete formation assay; Anne-Marie Zeeman and Clemens H. M Kocken from the Biomedical Primate Research Centre, Rijswijk (The Netherlands), for the P. cynomolgi in vitro prophylactic and radical cure assay; and Rachaneeporn Jenwithisuk from the Faculty of Tropical Medicine, Mahidol University, Bangkok (Thailand), for the Pv in vitro prophylactic and radical cure assay. We acknowledge the Medicines for Malaria Venture (projects MMV09/0002 and 08/0015), Technology Innovation Agency (TIA), the NIH (R01 AI103058 to D.A.F.) and the Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC) for financial support of this research. K.C. acknowledges support from the University of Cape Town, SAMRC, and South African Research Chairs Initiative of the Department of Science and Technology administered through the National Research Foundation. L.-M.B. and T.L.C. also acknowledge support of SHIP.

Original languageEnglish
Article numbere00012-18
Pages (from-to)1-16
Number of pages16
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Fingerprint

1-Phosphatidylinositol 4-Kinase
Plasmodium falciparum
South Africa
Malaria
Plasmodium
Solubility
Biomedical Research
Research
Technology
Finches
Tropical Medicine
Plasmodium vivax
Financial Support
Plasmodium berghei
Health
Thailand
Life Cycle Stages
Germ Cells
Pharmaceutical Preparations
Netherlands

Cite this

Brunschwig, C., Lawrence, N., Taylor, D., Abay, E., Njoroge, M., Basarab, G. S., ... Chibaleb, K. (2018). Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria. Antimicrobial Agents and Chemotherapy, 62(9), 1-16. [e00012-18]. https://doi.org/10.1128/AAC.00012-18
Brunschwig, Christel ; Lawrence, Nina ; Taylor, Dale ; Abay, Efrem ; Njoroge, Mathew ; Basarab, Gregory S. ; Le Manach, Claire ; Paquet, Tanya ; Cabrera, Diego Gonzàlez ; Nchinda, Aloysius T. ; De Kock, Carmen ; Wiesner, Lubbe ; Denti, Paolo ; Waterson, David ; Blasco, Benjamin ; Leroy, Didier ; Witty, Michael J. ; Donini, Cristina ; Duffy, James ; Wittlin, Sergio ; White, Karen L. ; Charman, Susan A. ; Jimenez-Diaz, Maria Belen ; Angulo-Barturen, Iñigo ; Herreros, Esperanza ; Gamo, Francisco Javier ; Rochford, Rosemary ; Mancama, Dalu ; Coetzer, Theresa L. ; Van der Watt, Mariëtte E. ; Reader, Janette ; Birkholtz, Lyn Marie ; Marsh, Kennan C. ; Solapure, Suresh M. ; Burke, John E. ; McPhail, Jacob A. ; Vanaerschot, Manu ; Fidock, David A. ; Fish, Paul V. ; Siegl, Peter ; Smith, Dennis A. ; Wirjanata, Grennady ; Noviyanti, Rintis ; Price, Ric N. ; Marfurt, Jutta ; Silue, Kigbafori D. ; Street, Leslie J. ; Chibaleb, Kelly. / Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria. In: Antimicrobial Agents and Chemotherapy. 2018 ; Vol. 62, No. 9. pp. 1-16.
@article{c3459d7fbda640d9a757bee1dc93b48e,
title = "Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria",
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-2Rnull 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.We acknowledge the following: Nesia Barnes and Warren Olifant from H3D, University of Cape Town (South Africa), for the ADME assays; Virgil Verhoog and Sumaya Salie from H3D, University of Cape Town (South Africa), for the P. falciparum blood stage assays; Trevor Finch from the Division of Pharmacology, University of Cape Town (South Africa), for assistance with the animal work; Michael Delves, Andrea Ruecker, and Robert E. Sinden from the Cell and Molecular Biology laboratory, Imperial College, London (United Kingdom), for the gamete formation assay; Anne-Marie Zeeman and Clemens H. M Kocken from the Biomedical Primate Research Centre, Rijswijk (The Netherlands), for the P. cynomolgi in vitro prophylactic and radical cure assay; and Rachaneeporn Jenwithisuk from the Faculty of Tropical Medicine, Mahidol University, Bangkok (Thailand), for the Pv in vitro prophylactic and radical cure assay. We acknowledge the Medicines for Malaria Venture (projects MMV09/0002 and 08/0015), Technology Innovation Agency (TIA), the NIH (R01 AI103058 to D.A.F.) and the Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC) for financial support of this research. K.C. acknowledges support from the University of Cape Town, SAMRC, and South African Research Chairs Initiative of the Department of Science and Technology administered through the National Research Foundation. L.-M.B. and T.L.C. also acknowledge support of SHIP.",
keywords = "1-phosphatidylinositol 4-kinase inhibitor, Absorption, Distribution metabolism, Drug discovery, Excretion, Human dose prediction, In vivo efficacy, Malaria, Pharmacokinetic/pharmacodynamic modeling, Pharmacokinetics, Plasmodium spp",
author = "Christel Brunschwig and Nina Lawrence and Dale Taylor and Efrem Abay and Mathew Njoroge and Basarab, {Gregory S.} and {Le Manach}, Claire and Tanya Paquet and Cabrera, {Diego Gonz{\`a}lez} and Nchinda, {Aloysius T.} and {De Kock}, Carmen and Lubbe Wiesner and Paolo Denti and David Waterson and Benjamin Blasco and Didier Leroy and Witty, {Michael J.} and Cristina Donini and James Duffy and Sergio Wittlin and White, {Karen L.} and Charman, {Susan A.} and Jimenez-Diaz, {Maria Belen} and I{\~n}igo Angulo-Barturen and Esperanza Herreros and Gamo, {Francisco Javier} and Rosemary Rochford and Dalu Mancama and Coetzer, {Theresa L.} and {Van der Watt}, {Mari{\"e}tte E.} and Janette Reader and Birkholtz, {Lyn Marie} and Marsh, {Kennan C.} and Solapure, {Suresh M.} and Burke, {John E.} and McPhail, {Jacob A.} and Manu Vanaerschot and Fidock, {David A.} and Fish, {Paul V.} and Peter Siegl and Smith, {Dennis A.} and Grennady Wirjanata and Rintis Noviyanti and Price, {Ric N.} and Jutta Marfurt and Silue, {Kigbafori D.} and Street, {Leslie J.} and Kelly Chibaleb",
year = "2018",
month = "9",
day = "1",
doi = "10.1128/AAC.00012-18",
language = "English",
volume = "62",
pages = "1--16",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "9",

}

Brunschwig, C, Lawrence, N, Taylor, D, Abay, E, Njoroge, M, Basarab, GS, Le Manach, C, Paquet, T, Cabrera, DG, Nchinda, AT, De Kock, C, Wiesner, L, Denti, P, Waterson, D, Blasco, B, Leroy, D, Witty, MJ, Donini, C, Duffy, J, Wittlin, S, White, KL, Charman, SA, Jimenez-Diaz, MB, Angulo-Barturen, I, Herreros, E, Gamo, FJ, Rochford, R, Mancama, D, Coetzer, TL, Van der Watt, ME, Reader, J, Birkholtz, LM, Marsh, KC, Solapure, SM, Burke, JE, McPhail, JA, Vanaerschot, M, Fidock, DA, Fish, PV, Siegl, P, Smith, DA, Wirjanata, G, Noviyanti, R, Price, RN, Marfurt, J, Silue, KD, Street, LJ & Chibaleb, K 2018, 'Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria', Antimicrobial Agents and Chemotherapy, vol. 62, no. 9, e00012-18, pp. 1-16. https://doi.org/10.1128/AAC.00012-18

Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria. / Brunschwig, Christel; Lawrence, Nina; Taylor, Dale; Abay, Efrem; Njoroge, Mathew; Basarab, Gregory S.; Le Manach, Claire; Paquet, Tanya; Cabrera, Diego Gonzàlez; Nchinda, Aloysius T.; De Kock, Carmen; Wiesner, Lubbe; Denti, Paolo; Waterson, David; Blasco, Benjamin; Leroy, Didier; Witty, Michael J.; Donini, Cristina; Duffy, James; Wittlin, Sergio; White, Karen L.; Charman, Susan A.; Jimenez-Diaz, Maria Belen; Angulo-Barturen, Iñigo; Herreros, Esperanza; Gamo, Francisco Javier; Rochford, Rosemary; Mancama, Dalu; Coetzer, Theresa L.; Van der Watt, Mariëtte E.; Reader, Janette; Birkholtz, Lyn Marie; Marsh, Kennan C.; Solapure, Suresh M.; Burke, John E.; McPhail, Jacob A.; Vanaerschot, Manu; Fidock, David A.; Fish, Paul V.; Siegl, Peter; Smith, Dennis A.; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Silue, Kigbafori D.; Street, Leslie J.; Chibaleb, Kelly.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 9, e00012-18, 01.09.2018, p. 1-16.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria

AU - Brunschwig, Christel

AU - Lawrence, Nina

AU - Taylor, Dale

AU - Abay, Efrem

AU - Njoroge, Mathew

AU - Basarab, Gregory S.

AU - Le Manach, Claire

AU - Paquet, Tanya

AU - Cabrera, Diego Gonzàlez

AU - Nchinda, Aloysius T.

AU - De Kock, Carmen

AU - Wiesner, Lubbe

AU - Denti, Paolo

AU - Waterson, David

AU - Blasco, Benjamin

AU - Leroy, Didier

AU - Witty, Michael J.

AU - Donini, Cristina

AU - Duffy, James

AU - Wittlin, Sergio

AU - White, Karen L.

AU - Charman, Susan A.

AU - Jimenez-Diaz, Maria Belen

AU - Angulo-Barturen, Iñigo

AU - Herreros, Esperanza

AU - Gamo, Francisco Javier

AU - Rochford, Rosemary

AU - Mancama, Dalu

AU - Coetzer, Theresa L.

AU - Van der Watt, Mariëtte E.

AU - Reader, Janette

AU - Birkholtz, Lyn Marie

AU - Marsh, Kennan C.

AU - Solapure, Suresh M.

AU - Burke, John E.

AU - McPhail, Jacob A.

AU - Vanaerschot, Manu

AU - Fidock, David A.

AU - Fish, Paul V.

AU - Siegl, Peter

AU - Smith, Dennis A.

AU - Wirjanata, Grennady

AU - Noviyanti, Rintis

AU - Price, Ric N.

AU - Marfurt, Jutta

AU - Silue, Kigbafori D.

AU - Street, Leslie J.

AU - Chibaleb, Kelly

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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-2Rnull 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.We acknowledge the following: Nesia Barnes and Warren Olifant from H3D, University of Cape Town (South Africa), for the ADME assays; Virgil Verhoog and Sumaya Salie from H3D, University of Cape Town (South Africa), for the P. falciparum blood stage assays; Trevor Finch from the Division of Pharmacology, University of Cape Town (South Africa), for assistance with the animal work; Michael Delves, Andrea Ruecker, and Robert E. Sinden from the Cell and Molecular Biology laboratory, Imperial College, London (United Kingdom), for the gamete formation assay; Anne-Marie Zeeman and Clemens H. M Kocken from the Biomedical Primate Research Centre, Rijswijk (The Netherlands), for the P. cynomolgi in vitro prophylactic and radical cure assay; and Rachaneeporn Jenwithisuk from the Faculty of Tropical Medicine, Mahidol University, Bangkok (Thailand), for the Pv in vitro prophylactic and radical cure assay. We acknowledge the Medicines for Malaria Venture (projects MMV09/0002 and 08/0015), Technology Innovation Agency (TIA), the NIH (R01 AI103058 to D.A.F.) and the Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC) for financial support of this research. K.C. acknowledges support from the University of Cape Town, SAMRC, and South African Research Chairs Initiative of the Department of Science and Technology administered through the National Research Foundation. L.-M.B. and T.L.C. also acknowledge support of SHIP.

AB - 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-2Rnull 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.We acknowledge the following: Nesia Barnes and Warren Olifant from H3D, University of Cape Town (South Africa), for the ADME assays; Virgil Verhoog and Sumaya Salie from H3D, University of Cape Town (South Africa), for the P. falciparum blood stage assays; Trevor Finch from the Division of Pharmacology, University of Cape Town (South Africa), for assistance with the animal work; Michael Delves, Andrea Ruecker, and Robert E. Sinden from the Cell and Molecular Biology laboratory, Imperial College, London (United Kingdom), for the gamete formation assay; Anne-Marie Zeeman and Clemens H. M Kocken from the Biomedical Primate Research Centre, Rijswijk (The Netherlands), for the P. cynomolgi in vitro prophylactic and radical cure assay; and Rachaneeporn Jenwithisuk from the Faculty of Tropical Medicine, Mahidol University, Bangkok (Thailand), for the Pv in vitro prophylactic and radical cure assay. We acknowledge the Medicines for Malaria Venture (projects MMV09/0002 and 08/0015), Technology Innovation Agency (TIA), the NIH (R01 AI103058 to D.A.F.) and the Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC) for financial support of this research. K.C. acknowledges support from the University of Cape Town, SAMRC, and South African Research Chairs Initiative of the Department of Science and Technology administered through the National Research Foundation. L.-M.B. and T.L.C. also acknowledge support of SHIP.

KW - 1-phosphatidylinositol 4-kinase inhibitor

KW - Absorption

KW - Distribution metabolism

KW - Drug discovery

KW - Excretion

KW - Human dose prediction

KW - In vivo efficacy

KW - Malaria

KW - Pharmacokinetic/pharmacodynamic modeling

KW - Pharmacokinetics

KW - Plasmodium spp

UR - http://www.scopus.com/inward/record.url?scp=85052242696&partnerID=8YFLogxK

U2 - 10.1128/AAC.00012-18

DO - 10.1128/AAC.00012-18

M3 - Article

VL - 62

SP - 1

EP - 16

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 9

M1 - e00012-18

ER -