Discovery of Highly Potent and Selective CXCR4 Inhibitors Using Protein Epitope Mimetics (PEM) Technology

Abstract

Novel, highly potent CXCR4 inhibitors with good pharmacokinetic properties were obtained by applying PEM technology starting from the naturally occurring ?-hairpin peptide polyphemusin II. The design involved incorporation of key residues from polyphemusin II into a macrocyclic template-bound ?-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized, resulting in CXCR4 inhibitors such as POL2438 and POL3026. Their activities were confirmed in a series of in vitro HIV-1 infection assays. Besides high selectivity for CXCR4, POL3026 had excellent plasma stability and favorable pharmacokinetic properties in dogs. In a murine model POL3026 was highly efficacious in hematopoietic stem cell mobilization. Hence, PEM-based CXCR4 inhibitors have the potential to become therapeutic agents for the treatment of HIV infections (as entry inhibitor), cancer (e.g. for inhibition of metastasis), stem cell transplant and inflammation.

The Intricate Role of CXCR4 in Cancer

“…BKT140 in combination with imatinib, a tyrosine-kinase inhibitor, was shown to overcome the protective effects of stroma in CML models (Fahham et al, 2012). POL6326 is another selective CXCR4 peptidomimetic antagonist developed based on protein epitope mimetics technology (DeMarco et al, 2006; Lederer et al, 2007). POL6326 is in phase II trial in MM patients (Schmitt et al, 2010).…”