Potent In Vitro Peptide Antagonists of the Thrombopoietin Receptor as Potential Myelofibrosis Drugs

Abstract Myelofibrosis (MF) is a life‐threatening blood cancer, with current drugs providing only symptomatic relief without altering the course of the disease. Thrombopoietin, an important cytokine for platelet production, signals via its receptor c‐Mpl that is upregulated in MF patients. Therefore, inhibition of this pathway may be a useful strategy to slow or stop progression of MF. Computational modeling and rational residue substitutions of a family of linear and cyclic peptides allow the identification of RQW as the essential motif for activity at the c‐Mpl receptor. The lead cyclic peptide 48 inhibits factor dependent Mpl cells with an IC 50 of 49 × 10 −9 m . In primary hematopoietic stem cells, 48 is able to stop the progression of CD34 + cells into megakaryocytes and another lead peptide has previously been shown to selectively ablate MF stem cells. These peptides represent important tools for further in vivo analysis and are an important step toward much needed disease‐modifying therapies for MF.