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CXCR4 heteromers

Conventional approach of blocking CXCR4 pathway based on existing hypothesis

Existing hypothesis: CXCR4 exists as monomers/homomers with identical signals

Real-world evidence of intracellular signaling enhancement by CXCR4 heteromers

When both agonists(CXCL12 and Agonist X) were incubated, intracellular signal was substantially enhanced compared to either agonist alone. (Fig.1)

No enhanced intracellular signal was detected when both agonists(CXCL12 and Agonist X) were incubated to the cell lines expressing either CXCR4 or GPCRx alone. (Fig.2, 3)

Novel hypothesis of CXCR4 heteromers and their intracellular signaling enhancement

CXCR4 forms heteromers with certain GPCRs resulting in distinct, often enhanced signals

Real- world evidence of intracellular signaling inhibition by CXCR4 / GPCRx inhibitors

In the absence of antagonist, both agonists(CXCL12 and Agonist X) induced an enhanced intracellular signal compared to when each agonist was treated alone. (Fig. 1)

The enhanced intracellular signal was inhibited differently depending on the types and combinations of compounds that were treated. (Fig.2, 3, 4)

Existing CXCR4 antagonist did not show complete inhibition when CXCR4 heteromers were present. (Fig.2)

The enhanced intracellular signal was inhibited differently depending on the types and combinations of compounds that were treated. (Fig.2, 3, 4)

Specific combinations of antagonists completely suppressed the enhanced signals. (Fig.4)

Innovative approach of blocking CXCR4 pathway based on novel hypothesis

Treatment of CXCR4 inhibitors alone results in limited clinical efficacy.

Appropriate combination of inhibitors are needed for effective blockade of CXCR4 pathway.