Myelofibrosis is an incurable blood cancer with an average life expectancy of five years. There are no drug treatments that affect the course of the disease and only palliative drug treatments are available. Bone marrow transplants are the only current treatment, but it carries a considerable risk of life-threatening side effects and has very high cost. Recently, interactions between thrombopoietin (TPO) and its receptor have been shown to play a role in the development and progression of myeloproliferative neoplasms including myelofibrosis. These observations have led to the development of strategies to disrupt the association of TPO with its receptor as a means of targeting MF hematopietic stem cells (HSC) and progenitor cells (HPC). TPO is a ligand critical for maintenance of HSC quiescence, survival and proliferation and is the primary regulator of megakaryocyte and platelet production.
A 20-amino acid cyclic peptide TPO receptor antagonist (LCP4), was created by Drs. Haylock, Tarasova, and Winkler in Melbourne, Australia. LCP4 binds directly to TPO receptor (MPL) at exactly the same location as native TPO and is highly antagonistic to the MPL receptor and to cord blood CD34+ cell proliferation and megakaryocyte differentiation.
Different types of cyclization were investigated to create new versions of LCP4. Introduced modifications resulted in peptides with different size of the cyclic part. The chemistry utilized to prepare cyclic peptides along with biological evaluation will be presented.