A new class of CXCR4 modulators for metastasis and inflammation.
- Selective for only one allosteric site on CXCR4.
- Lower adverse effects.
Multiple myeloma, acute myeloid leukemia, HIV, and rheumatoid arthritis all involve the G-protein receptor CXCR4. Currently, there is only one FDA-approved CXCR4 antagonist, AMD3100, but the compound has cardiotoxicity issues related to its ability to block Ca2+ flux. Researchers at Emory University have identified ZINC72372983 as having anti-inflammatory effects and upon further development, a 100-fold improvement in binding affinity. This invention could contribute to the immunotherapy drug market which was $130.3 billion in 2019 and is expected to reach $204.4 billion by 2025 with a CAGR of 7.9% 2019-to 2025 (BCC Research PIIM249A).
Researchers screened for compounds that bind in allosteric sites to find compounds that module the receptor without having adverse effects. Through ligand-based screening, docking ADMET, and PAINS filters the researchers found 7 compounds from a ZINC database that were taken forward in vitro assay. In vitro assay revealed 4 of the 7 compounds had binding constants between 100-10 nm via fluorescence in moderate throughput assay. These 4 were then put through in vitro functional assay revealing that the compound ZINC72372983 had the best inhibitory efficacy against the chemotaxis between CXCR4 and CXCL12.
Animal testing was conducted.
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