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 Belén Jiménez-Díaz, 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

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.

Original languageEnglish
Article numbere00012-18
Number of pages16
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

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

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), [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. ; Jiménez-Díaz, Maria Belén ; 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.
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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.",
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 Jim{\'e}nez-D{\'i}az, {Maria Bel{\'e}n} 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",
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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, Jiménez-Díaz, 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. 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.; Jiménez-Díaz, Maria Belén; 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.

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 - Jiménez-Díaz, Maria Belén

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.

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.

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

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 1098-6596

IS - 9

M1 - e00012-18

ER -