Background:

IC50: 194 nM

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.

In vitro: 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].

In vivo: 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].

Clinical trial: Up to now, ATI-2341 is still in the preclinical development stage.

Reference:
[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.