Tetrahydroisoquinoline-Based Small Molecule Inhibitors of the Chemokine Receptor CXCR4

Abstract ID 127096 Poster Board 291 CXCR4 is a physiologically important chemokine receptor that is expressed on hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs), and various immune cell subsets. These CXCR4-expressing cells traffic along concentration gradients of the sole endogenous chemokine ligand CXCL12, which disseminates from stromal niches in lymph nodes, lung, liver, and bone marrow. As a prime example, CXCL12 secretion from bone-associated stroma drives migration and retention of CXCR4-expressing cells, especially HSCs, in the bone marrow. Additionally the CXCR4/CXCL12 axis is pathophysiologically hijacked by various cancer types, over 50 of which are characterized by dramatic CXCR4 and/or CXCL12 upregulation. Roughly half of all RCC tumors, for example, are driven by deactivating mutations in tumor suppressor VHL, which negatively regulates CXCR4 and CXCL12 expression. This chemokine network misregulation (1) hyperactivates CXCR4 cancer cell survival signaling, (2) overstimulates intratumoral infiltration of CXCR4-expressing EPCs and immunosuppressive subsets (e.g., reulatory T cells, TRegs, and myeloid-derived suppressor cells, MDSCs), and (3) pushes into overdrive the metastatic expansion of CXCR4-expressing cancer cells to distant CXCL12-secreting niches. As a consequence, there has been significant interest and progress over the last 25 years on the development of bicyclams, cyclic peptides, and small molecules that inhibit CXCR4-CXCL12 interactions. Although bicyclam plerixafor and cyclic peptide motixafortide have been approved by the FDA for HSC mobilization, both require administration via injection, and neither have unlocked the full therapeutic potential of CXCR4 antagonists in oncology. To address this gap, our team has been developing orally bioavailable, tetrahydroisoquinoline-based small molecule CXCR4 antagonists since the late 2000's. Through organic synthesis and pharmacological evaluation of nearly 500 compounds, a foundational understanding of associated structure-activity relationships has emerged. However, increased understanding is often paired with the realization of greater complexity, and that is certainly operative here. With our robust tool kit of small molecules and a growing panel of in vitro assays designed to measure different aspects of CXCR4 biology, a significant component of this collaborative research program will be dedicated to elucidating the nuances of complex CXCR4 function. In parallel, our best-in-class orally bioavailable CXCR4 antagonists will continue to be progressed through the pre-clinical pipeline and IND-enabling studies. Thank you to Biolocity and Winship Cancer Institute of Emory University for supporting a portion of this research.