Skip to main content

JOSD1 as a novel targeted therapy for JAK20V617F dependent myeloproliferative neoplasms

Dr. Buhrlage

Sara Buhrlage

PhD

Dana-Farber Cancer Institute

Project Term: March 2, 2022 - March 1, 2023

Mutations in JAK2 are the most prevalent genetic event in myeloproliferative neoplasms (MPNs). Drugs that inhibit mutated JAK2 provide clinical benefit, however their impairment of non-mutated JAK2, which normal cells require, limits their clinical usefulness. We propose a strategy to target mutated JAK2 for degradation, using the cell's intracellular machinery to do so, while sparing non-mutated JAK2.

Lay Abstract

Mutations in a gene called JAK2 are the most prevalent genetic event in myeloproliferative neoplasms (MPNs), a group of diseases defined by overproduction of one or more kinds of blood cells, including red cells, white cells, and platelets, by bone marrow. Small molecule inhibitors of the activity of mutated JAK2 provide clinical benefit, however their impairment of the function of the non-mutated form of JAK2, which normal cells require, limits their clinical usefulness. Here, we propose a strategy to target mutated JAK2 for degradation, using the cell's intracellular machinery to do so, while sparing non-mutated JAK2. We show that inhibition of the deubiquitinase (DUB) JOSD1, leads to selective degradation of mutated JAK2. Specifically, we show that inhibitors of JOSD1 selectively inhibit the growth of mutated JAK2-driven malignant cells without impacting the growth of cells expressing non-mutated JAK2. In this application from our multidisciplinary team of chemists, biologists and clinicians, we propose to develop JOSD1 inhibitors characterized by improved potency and selectivity toward JOSD1 as a therapeutic target for treatment of MPNs harboring mutated JAK2. These studies provide a novel strategy to obtain a real therapeutic window in targeting mutated JAK2 in MPN and potentially fill a critically unmet clinical need.

Program
Special Grants
To All Projects