A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis

NIP-004 is a novel synthetic compound developed to display human thrombopoietin (TPO) receptor (c-Mpl) agonist activity. NIP-004 displays species specificity, stimulating proliferation or differentiation of human c-Mpl–expressing cells such as UT-7/TPO and human CD34+ cells but not murine c-Mpl–expr...

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Bibliographic Details
Published in:Blood 2006-06, Vol.107 (11), p.4300-4307
Main Authors: Nakamura, Takanori, Miyakawa, Yoshitaka, Miyamura, Atsushi, Yamane, Akiko, Suzuki, Hidenori, Ito, Mamoru, Ohnishi, Yasuyuki, Ishiwata, Norihisa, Ikeda, Yasuo, Tsuruzoe, Nobutomo
Format: Article
Language:English
Subjects:
Animals
Blood Platelets - cytology
Cell Count
Cell Line, Tumor
Cord Blood Stem Cell Transplantation
Graft Survival
Histidine
Humans
Megakaryocytes - cytology
Mice
Mice, SCID
Mutation
Proto-Oncogene Proteins - agonists
Proto-Oncogene Proteins - genetics
Receptors, Cytokine - agonists
Receptors, Cytokine - genetics
Receptors, Thrombopoietin
Thrombopoiesis - drug effects
Transplantation, Heterologous
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Summary:NIP-004 is a novel synthetic compound developed to display human thrombopoietin (TPO) receptor (c-Mpl) agonist activity. NIP-004 displays species specificity, stimulating proliferation or differentiation of human c-Mpl–expressing cells such as UT-7/TPO and human CD34+ cells but not murine c-Mpl–expressing cells or cynomolgus monkey cells. To test the mechanism of its action, we constructed mutant forms of c-Mpl; murine c-MplL490H dis-played a response to NIP-004, whereas human c-MplH499L lost this response, indicating that histidine in the transmembrane domain of c-Mpl is essential for its activity. Because histidine is not present in the c-Mpl transmembrane domain of rats, hamsters, rhesus macaques, and cynomolgus monkeys, we examined the in vivo efficacy of NIP-004 using mice that received xenotransplants. In immunodeficient nonobese diabetic (NOD)/Shi-scid, IL-2Rγnull (NOG) mice receiving transplants of umbilical cord blood–derived CD34+ cells, NIP-004 increased human megakaryoblasts, mature megakaryocytes, and circulating human platelets 6-fold, the latter being morphologically and functionally indistinguishable from normal human platelets. These observations indicate that NIP-004 is a novel human c-Mpl activator and induces human thrombopoiesis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2005-11-4433