A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy.

Autor: Ross BD; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA. bdross@umich.edu.; Department of Biological Chemistry, University of Michigan School of Medicine, Ann Arbor, MI, USA. bdross@umich.edu., Jang Y; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Welton A; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Bonham CA; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Palagama DSW; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Heist K; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Boppisetti J; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Imaduwage KP; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Robison T; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA., King LR; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Zhang EZ; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Amirfazli C; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Luker KE; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Lee WY; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA., Luker GD; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA., Chenevert TL; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA., Van Dort ME; Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Aug 17; Vol. 13 (1), pp. 4730. Date of Electronic Publication: 2022 Aug 17.
DOI: 10.1038/s41467-022-32486-8
Abstrakt: Activation of compensatory signaling nodes in cancer often requires combination therapies that are frequently plagued by dose-limiting toxicities. Intestinal lymphatic drug absorption is seldom explored, although reduced toxicity and sustained drug levels would be anticipated to improve systemic bioavailability. A potent orally bioavailable multi-functional kinase inhibitor (LP-182) is described with intrinsic lymphatic partitioning for the combined targeting of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways without observable toxicity. We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications.
(© 2022. The Author(s).)
Databáze: MEDLINE
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