Under normal physiological conditions, chemokine receptor CXCR4 is mainly expressed on the surface of hematopoietic stem cell lineages, while its cognate chemokine ligand CXCL12 is predominantly secreted by stromal cells in the bone marrow, lymph nodes, liver, and lungs. Under the pathophysiological conditions driven by &gt; 48 different cancers however, CXCR4 and CXCL12 are substantially upregulated in tumor tissue relative to healthy tissue. Overactivation of CXCR4/CXCL12-mediated cell signaling and chemotactic migration has 3 chief consequences: 1) tumor-localized stimulation of autocrine and paracrine proliferation cascades, 2) CXCR4+ immunosuppressive regulatory T cell and myeloid-derived suppressor cell infiltration of tumor microenvironments, and 3) CXCR4+ cancer cell metastasis to distant CXCL12-rich niches. Although this implicates inhibition of the CXCR4/CXCL12 axis as an attractive therapeutic strategy in oncology, the utility of current clinical antagonists is limited due to poor pharmacokinetics and off-target activities. Accordingly, a series of tetrahydroisoquinoline-containing CXCR4 antagonists were designed to address these shortcomings. Out of &gt; 250 compounds synthesized by our team, the in vitro activity profiles of the top 8 inhibitors are competitive with or superior to current clinical candidate AMD11070. These activity profiles, as well as the results of in vivo pharmacokinetic and pharmacodynamic experiments will be disclosed.

Discovery of tetrahydroisoquinoline-containing CXCR4 antagonists with enhanced ADMET properties and evaluation as anti-cancer agents

2019 Fall National Meeting

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