ati-2341 is a cxcr4 allosteric agonist.chemokine cxc-type receptor 4 (cxcr4) and its ligand cxcl12 mediate the retention of polymorphonuclear neutrophils and hematopoietic stem and progenitor cells in the bone marrow. drugs disrupting cxcl12-mediated chemoattraction of cxcr4-expressing cells are useful for hematopoietic stem and progenitor cells (hspcs) collection.
ati-2341 could inhibit nkh477-induced camp accumulation in cxcr4-hek cells dose-dependently, but showed no effect in naive hek-293 parental cells. pretreatment of cxcr4- hek cells with pertussis toxin completely abrogated the ability of ati-2341 to inhibit camp accumulation. ati-2341 could also induce a dose-dependent increase in intracellular calcium in cells transfected with wild-type cxcr4 whereas having no effect on untransfected cells. activation of such signaling pathway by ati-2341 was dependent on a fully functional cxcr4 receptor since ati-2341 was not able to mobilize calcium in cells transfected with a cxcr4 receptor variant [1].
ati-2341 could induce dose-dependent peritoneal recruitment of polymorphonuclear neutrophils (pmns) when i.p. administered to mice. however, when systemically administered by i.v. bolus, ati-2341 acted as an antagonist and could dose-dependently mediate release of pmns from the bone marrow of mice and cynomolgus monkeys. in addition, ati-2341-mediated release of granulocyte/macrophage progenitor cells from the bone marrow was further confirmed by colony-forming assays [1].
| Target | Value |
CXCR4
(in CCRF-CEM cells) | < td style="border-bottom: 1px dotted #ccc;padding: 5px;"> 194 nM(EC50)
[1] tchernychev b et al. discovery of a cxcr4 agonist pepducin that mobilizes bone marrow hematopoietic cells. proc natl acad sci u s a.2010 dec 21;107(51):22255-9.
