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ART714 is a best-in-class antileukemic 2-carbon-linked dimeric artemisinin derivative.
Kagan, Amanda B; Moses, Blake S; Lapidus, Rena; Mott, Bryan T; Rai, Ganesha; Anders, Nicole M; Hoag, Stephen W; Rudek, Michelle A; Civin, Curt I.
Afiliación
  • Kagan AB; Department of Medicine, Division of Clinical Pharmacology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Moses BS; Department of Oncology, School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB1 Room 1M52, Baltimore, MD, 21231-1000, USA.
  • Lapidus R; Departments of Pediatrics and Physiology, School of Medicine, Center for Stem Cell Biology and Regenerative Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, BRB14-021, 655 W Baltimore St, Baltimore, MD, 21201, USA.
  • Mott BT; Keros Therapeutics, Inc., Lexington, MA, USA.
  • Rai G; Department of Medicine, School of Medicine, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
  • Anders NM; Department of Neurosurgery, Wake Forest Baptist Health, Winston-Salem, NC, USA.
  • Hoag SW; Department of Pre-clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
  • Rudek MA; Department of Oncology, School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRB1 Room 1M52, Baltimore, MD, 21231-1000, USA.
  • Civin CI; Takeda Pharmaceutical Company, San Diego, CA, USA.
Cancer Chemother Pharmacol ; 92(1): 39-50, 2023 07.
Article en En | MEDLINE | ID: mdl-37249624
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Artemisininas / Antimaláricos / Antineoplásicos Límite: Humans Idioma: En Revista: Cancer Chemother Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Artemisininas / Antimaláricos / Antineoplásicos Límite: Humans Idioma: En Revista: Cancer Chemother Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania