CXCR4 is a pathophysiologically important chemokine receptor that is expressed on various immune cell subsets. These CXCR4⁺ cells traffic along concentration gradients of the sole endogenous chemokine ligand CXCL12, which disseminates predominantly from stromal niches in lymph nodes, lung, liver, and bone marrow. The CXCR4/CXCL12 axis is hijacked by various cancer types, ≥48 of which are characterized by dramatic CXCR4 and/or CXCL12 upregulation. This chemokine network misregulation causes hyperactivation of CXCR4-mediated processes, leading to three chief consequences: 1) excessive stimulation of CXCR4⁺ cancer cell survival and proliferation signaling, 2) metastatic expansion of CXCR4⁺ cancer cells to secondary, CXCL12-rich sites, and 3) intratumoral infiltration of CXCR4⁺ immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. Accordingly, inhibitors of the CXCR4/CXCL12 axis have significant therapeutic potential against cancer progression. However, current CXCR4 inhibitors are severely limited by off-target activities and suboptimal pharmacokinetic profiles. To address these deficiencies, we synthesized >350 tetrahydroisoquinoline-based small molecule CXCR4 antagonists and pharmacologically evaluated them for on-target potency, off-target liabilities, permeability, and metabolic stability in vitro. Several compounds exhibiting excellent in vitro activity profiles further demonstrated superior mouse pharmacokinetic properties to Mavorixafor, a small molecule CXCR4 antagonist under clinical development. These improved pharmacokinetic properties translated to significantly enhanced anticancer activity in mouse models of renal cell carcinoma. These efforts ultimately led to the identification of EMU-116 as a clinical candidate with robust therapeutic potential against various tumor types.

Priscilla Davidson

Appearances