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

Author

Listed:
  • Brian D. Ross

    (University of Michigan School of Medicine
    University of Michigan School of Medicine)

  • Youngsoon Jang

    (University of Michigan School of Medicine)

  • Amanda Welton

    (University of Michigan School of Medicine)

  • Christopher A. Bonham

    (University of Michigan School of Medicine)

  • Dilrukshika S. W. Palagama

    (University of Michigan School of Medicine)

  • Kevin Heist

    (University of Michigan School of Medicine)

  • Jagadish Boppisetti

    (University of Michigan School of Medicine)

  • Kasun P. Imaduwage

    (University of Michigan School of Medicine)

  • Tanner Robison

    (University of Michigan School of Medicine
    University of Michigan)

  • Leah R. King

    (University of Michigan School of Medicine)

  • Edward Z. Zhang

    (University of Michigan School of Medicine)

  • Cyrus Amirfazli

    (University of Michigan School of Medicine)

  • Kathryn E. Luker

    (University of Michigan School of Medicine)

  • Winston Y. Lee

    (University of Michigan School of Medicine)

  • Gary D. Luker

    (University of Michigan School of Medicine
    University of Michigan School of Medicine)

  • Thomas L. Chenevert

    (University of Michigan School of Medicine)

  • Marcian E. Van Dort

    (University of Michigan School of Medicine)

Abstract

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.

Suggested Citation

  • Brian D. Ross & Youngsoon Jang & Amanda Welton & Christopher A. Bonham & Dilrukshika S. W. Palagama & Kevin Heist & Jagadish Boppisetti & Kasun P. Imaduwage & Tanner Robison & Leah R. King & Edward Z., 2022. "A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32486-8
    DOI: 10.1038/s41467-022-32486-8
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    References listed on IDEAS

    as
    1. Haijuan Yang & Derek G. Rudge & Joseph D. Koos & Bhamini Vaidialingam & Hyo J. Yang & Nikola P. Pavletich, 2013. "mTOR kinase structure, mechanism and regulation," Nature, Nature, vol. 497(7448), pages 217-223, May.
    2. Haipeng Liu & Kelly D. Moynihan & Yiran Zheng & Gregory L. Szeto & Adrienne V. Li & Bonnie Huang & Debra S. Van Egeren & Clara Park & Darrell J. Irvine, 2014. "Structure-based programming of lymph-node targeting in molecular vaccines," Nature, Nature, vol. 507(7493), pages 519-522, March.
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