Journal article

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

Monika Szabo, Wioleta Kowalczyk, Anna Tarasova, Jessica Andrade, Cheang Ly Be, Roger Mulder, Jacinta White, Adam G Meyer, Kjiana E Schwab, Kellie Cartledge, Tu C Le, Anoja Wickrama Arachchilage, Xiaoli Wang, Ronald Hoffman, Susan K Nilsson, David N Haylock, David A Winkler

ADVANCED THERAPEUTICS | WILEY | Published : 2021

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 IC50 of 49 × 10−9 m. In primary hematopoietic stem cells, ..

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University of Melbourne Researchers