Novel Piperidine-Amide Derivatives as CXCR4 Modulators

Application

A new class of CXCR4 modulators for metastasis and inflammation.

Key Benefits

Selective for only one allosteric site on CXCR4.
Lower adverse effects.

Market Summary

Activation of the CXCR4 receptor triggers multiple signaling pathways that orchestrate cell migration, hematopoiesis and cell homing, and retention in the bone marrow. However, CXCR4 also directly controls cell proliferation of non-hematopoietic cells, induces inflammation, and is implicated in a number of diseases including multiple myeloma, acute myeloid leukemia, HIV, rheumatoid arthritis and others. Currently, only one FDA approved CXCR4 inhibitor is on the market for blood cancers, but its use is limited to due to adverse cardiotoxicity. Hence, the development of new CXCR4 antagonists with increase potency and reduced toxicity to healthy tissues could broaden the potential of the receptor, leading to new treatments across many disease indications.

Technical Summary

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 then put through in vitro functional assay revealing that the compound ZINC72372983 had the best inhibitory efficacy against the chemotaxis between CXCR4 and CXCL12.