ART714 is a best-in-class antileukemic 2-carbon-linked dimeric artemisinin derivative

Purpose It has become increasingly clear that new multiagent combination regimens are required to improve survival rates in acute myeloid leukemia (AML). We recently reported that ART631, a first-in-class 2-carbon-linked artemisinin-derived dimer (2C-ART), was not only efficacious as a component of a novel three-drug combination regimen to treat AML, but, like other synthetic artemisinin derivatives, demonstrated low clinical toxicity. However, we ultimately found ART631 to have suboptimal solubility and stability properties, thus limiting its potential for clinical development. Methods We assessed 22 additional 2C-ARTs with documented in vivo antimalarial activity for antileukemic efficacy and physicochemical properties. Our strategy involved culling out 2C-ARTs inferior to ART631 with respect to potency, stability, and solubility in vitro, and then validating in vivo pharmacokinetics, pharmacodynamics, and efficacy of one 2C-ART lead compound. Results Of the 22 2C-ARTs, ART714 was found to have the most optimal in vitro solubility, stability, and antileukemic efficacy, both alone and in combination with the BCL2 inhibitor venetoclax (VEN) and the kinase inhibitor sorafenib (SOR). ART714 was also highly effective in combination with VEN and the FMS-like tyrosine kinase 3 inhibitor gilteritinib (GILT) against MOLM14 AML xenografts. Conclusion We identified ART714 as our best-in-class antileukemic 2C-ART, based on in vitro potency and pharmacologic properties. We established its in vivo pharmacokinetics and demonstrated its in vitro cooperativity with VEN and SOR and in vivo activities of combinations of ART714, VEN, and GILT. Additional research is indicated to define the optimal niche for the use of ART714 in treatment of AML..

Medienart:

E-Artikel

Erscheinungsjahr:

2023

Erschienen:

2023

Enthalten in:

Zur Gesamtaufnahme - volume:92

Enthalten in:

Cancer chemotherapy and pharmacology - 92(2023), 1 vom: 30. Mai, Seite 39-50

Sprache:

Englisch

Beteiligte Personen:

Kagan, Amanda B. [VerfasserIn]
Moses, Blake S. [VerfasserIn]
Lapidus, Rena [VerfasserIn]
Mott, Bryan T. [VerfasserIn]
Rai, Ganesha [VerfasserIn]
Anders, Nicole M. [VerfasserIn]
Hoag, Stephen W. [VerfasserIn]
Rudek, Michelle A. [VerfasserIn]
Civin, Curt I. [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

Themen:

Artemisinin
Leukemia
Pharmacology

Anmerkungen:

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s00280-023-04539-2

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2143819552

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