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

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. Zhang, Cyrus Amirfazli, Kathryn E. Luker, Winston Y. Lee, Gary D. Luker, Thomas L. Chenevert and Marcian E. Van Dort
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Brian D. Ross: 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
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
Thomas L. Chenevert: University of Michigan School of Medicine
Marcian E. Van Dort: University of Michigan School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32486-8

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