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-expressing cells or cynomolgus monkey cells. To test the mechanism of its action, we constructed mutant forms of c-Mpl; murine c-Mpl(L490H) dis-played a response to NIP-004, whereas human c-Mpl(H499L) 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-2Rgamma(null) (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.
Nakamura
Takanori
T
Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries, Ltd, 1470 Shiraoka, Saitama 349-0294, Japan. tnakamura@nissanchem.co.jp
Miyakawa
Yoshitaka
Y
Miyamura
Atsushi
A
Yamane
Akiko
A
Suzuki
Hidenori
H
Ito
Mamoru
M
Ohnishi
Yasuyuki
Y
Ishiwata
Norihisa
N
Ikeda
Yasuo
Y
Tsuruzoe
Nobutomo
N
D000818:Animals; D001792:Blood Platelets / Q000166:cytology; D002452:Cell Count; D045744:Cell Line, Tumor; D036101:Cord Blood Stem Cell Transplantation; D006085:Graft Survival; D006639:Histidine; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000819:agonists* / Q000235:genetics; D018121:Receptors, Cytokine / Q000819:agonists* / Q000235:genetics; D053628:Receptors, Thrombopoietin; D034061:Thrombopoiesis / Q000187:drug effects*; D014183:Transplantation, Heterologous
D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D006639:Histidine