Potent in vitro peptide antagonists of the thrombopoietin receptor as potential myelofibrosis drugs

<p dir="ltr">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. </p><p dir="ltr">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 IC50 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. </p><p dir="ltr">These peptides represent important tools for further in vivo analysis and are an important step toward much needed disease-modifying therapies for MF.</p>