A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
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Updated: Sep 1, 2025
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Published on: June 6, 2025
Brian D Ross1,2, Youngsoon Jang3, Amanda Welton3
1Department of Radiology and the Center for Molecular Imaging, University of Michigan School of Medicine, Ann Arbor, MI, USA. bdross@umich.edu.
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.
Insights
A novel orally bioavailable kinase inhibitor, LP-182, targets both PI3K and MAPK pathways. This lymphatropic therapy demonstrates efficacy in myelofibrosis models with reduced toxicity, offering a new approach for cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Drug Delivery
Background:
- Cancer therapies often involve combination treatments with significant dose-limiting toxicities.
- Intestinal lymphatic drug absorption is an underutilized route that could enhance bioavailability and reduce systemic toxicity.
Purpose of the Study:
- To describe a novel orally bioavailable multi-functional kinase inhibitor (LP-182) with intrinsic lymphatic partitioning.
- To evaluate the efficacy and safety of LP-182 in targeting phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways.
Main Methods:
- Characterization of LP-182's synthetic and physiochemical properties for lymphatic uptake.
- Demonstration of selectivity and therapeutic efficacy in animal models of myelofibrosis.
- Assessment of downstream kinase activation, disease phenotype amelioration, and survival rates.
Main Results:
- LP-182 effectively targets both PI3K and MAPK pathways without observable toxicity.
- Therapeutic efficacy was confirmed through reduced kinase activation and improved disease phenotypes in myelofibrosis models.
- Improved survival rates were observed in treated animal models.
Conclusions:
- LP-182 represents a potent, orally bioavailable, and non-toxic therapeutic agent for targeting key cancer signaling pathways.
- Lymphatic drug uptake strategies, like that of LP-182, hold promise for improving drug delivery and patient outcomes.
- Further research into lymphatropic therapy can impact various human diseases.
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