The Development Process for Discovery and Clinical Advancement of Modern Antimalarials

Trent D. Ashton, Shane Devine, Jorg Mohrle, Benoît Laleu, Jeremy N. Burrows, Susan Charman, Darren Creek, Brad E Sleebs

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Malaria is a devastating disease caused by Plasmodium parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the Plasmodium parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life–cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.
Original languageEnglish
JournalJournal of Medicinal Chemistry
DOIs
Publication statusAccepted/In press - Aug 2019

Cite this

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title = "The Development Process for Discovery and Clinical Advancement of Modern Antimalarials",
abstract = "Malaria is a devastating disease caused by Plasmodium parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the Plasmodium parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life–cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.",
author = "Ashton, {Trent D.} and Shane Devine and Jorg Mohrle and Beno{\^i}t Laleu and Burrows, {Jeremy N.} and Susan Charman and Darren Creek and Sleebs, {Brad E}",
year = "2019",
month = "8",
doi = "10.1021/acs.jmedchem.9b00761",
language = "English",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
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The Development Process for Discovery and Clinical Advancement of Modern Antimalarials. / Ashton, Trent D.; Devine, Shane; Mohrle, Jorg; Laleu, Benoît; Burrows, Jeremy N.; Charman, Susan; Creek, Darren; Sleebs, Brad E.

In: Journal of Medicinal Chemistry, 08.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The Development Process for Discovery and Clinical Advancement of Modern Antimalarials

AU - Ashton, Trent D.

AU - Devine, Shane

AU - Mohrle, Jorg

AU - Laleu, Benoît

AU - Burrows, Jeremy N.

AU - Charman, Susan

AU - Creek, Darren

AU - Sleebs, Brad E

PY - 2019/8

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N2 - Malaria is a devastating disease caused by Plasmodium parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the Plasmodium parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life–cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.

AB - Malaria is a devastating disease caused by Plasmodium parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the Plasmodium parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life–cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.

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DO - 10.1021/acs.jmedchem.9b00761

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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