Lymophatic-absorbed multi-kinase inhibitor for myelofibrosis

An orally bioavailable multi-kinase inhibitor that is primarily absorbed through gastrointestinal lymphatic vessels due to its association with lipoproteins could help treat myelofibrosis while minimizing toxicity. The compound consists of an analog of the dual PI3K/mTOR inhibitor GSK2126458 attached to an analog of the MEK inhibitor PD0325901 via a short PEG linker, yielding a combined compound that inhibits PI3K, mTOR, MEK and RAF kinases, and has an approximately 8:1 lymph to plasma ratio after oral dosing in mice.

In a mouse model of myelofibrosis induced by transplant of hematopoietic stem and progenitor cells (HSPCs) expressing a mutant thrombopoietin receptor, the compound decreased splenomegaly, extramedullary hematopoiesis, bone marrow cell density and AKT and ERK1/2 signaling in bone marrow cells and splenocytes compared with vehicle; the compound also extended survival until the end of study period at 50 days post-transplant, whereas all animals that received vehicle had to be euthanized. ...