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

Area of Science:

• * Medicinal Chemistry
• * Hematology
• * Oncology

Background:

• * Acute myeloid leukemia (AML) necessitates novel combination therapies to improve patient survival rates.
• * Previous research identified ART631, a 2-carbon-linked artemisinin derivative (2C-ART), as a potentially effective AML treatment with low toxicity.
• * ART631 exhibited suboptimal solubility and stability, hindering its clinical development.

Purpose of the Study:

• * To evaluate 22 novel 2C-ART compounds for antileukemic efficacy and improved physicochemical properties.
• * To identify a lead 2C-ART compound with superior potency, stability, and solubility compared to ART631.
• * To validate the in vivo pharmacokinetics, pharmacodynamics, and efficacy of the lead 2C-ART candidate.

Main Methods:

• * Screening of 22 2C-ARTs with known antimalarial activity for antileukemic potential in vitro.
• * Selection of compounds based on superior in vitro potency, solubility, and stability.
• * In vivo validation of pharmacokinetics, pharmacodynamics, and efficacy of the lead compound, including combination studies.

Main Results:

• * ART714 demonstrated the most optimal in vitro solubility, stability, and antileukemic efficacy among the tested 2C-ARTs.
• * ART714 showed significant efficacy both as a single agent and in combination with venetoclax (VEN) and sorafenib (SOR).
• * ART714, in combination with VEN and gilteritinib (GILT), proved highly effective against MOLM14 AML xenografts in vivo.

Conclusions:

• * ART714 has been identified as a best-in-class antileukemic 2C-ART, exhibiting superior in vitro potency and favorable pharmacologic properties.
• * In vivo studies confirmed the pharmacokinetic profile and demonstrated synergistic activity with VEN and SOR, and efficacy with VEN and GILT.
• * Further investigation is warranted to determine the optimal clinical application of ART714 in AML treatment regimens.