Nilotinib Exhibits an in Vitro Antiviral Activity Against Human Cytomegalovirus (HCMV): Potential Clinical Applications

Abstract 4666

Chronic myeloid leukemia (CML) is a clonal disorder associated with chromosomal translocation t (9; 22), which produces the Philadelphia chromosome. The fusion gene encodes for the chimeric oncoprotein BCR-ABL, associated with deregulated constitutive tyrosine kinase (TK) activity, leading to leukemogenesis. Imatinib mesylate, the first potent selective inhibitor of BCR-ABL TK, has revolutionized the current management of CML. The second generation TK inhibitor (TKI) Nilotinib (Novartis, East Hanover, NJ) is an aminopyrimidine derivative of imatinib with an increased binding affinity to the chimeric p210 BCR-ABL. Nilotinib is active in imatinib-resistant or -intolerant patients in chronic phase, accelerated phase (AP), and blast crisis (BC) CML.

Allogeneic stem cell transplantation (SCT) is currently reserved for patients(pts) in CP after the failure of second line TKI or for patients in advanced phase disease.SCT remains the treatment of choice in patients with Ph⁺ALL. TKIs can be used successfully pre -SCT as a bridge to SCT in advanced disease and post-SCT in order to prevent disease recurrence. HCMV is one of the leading causes of morbidity and mortality post SCT in particular in pts transplanted for advance CML and pts with graft vs. host disease (GVHD) While preemptive antiviral therapy has reduced the occurrence of HCMV disease post SCT, the use of all currently available antiviral drugs is often limited by toxicity, low oral bioavailability, and drug resistance.

The mechanisms facilitating HCMV entry into the host cells are not clearly understood. Blocking of the platelet – derived growth factor receptor-α (PDGFRα) has been shown to inhibit HCMV internalization and gene expression. Recently, Imatinib have been shown to inhibit PDGFRα phosphorylation. As Nilotinib is a more potent PDGFR inhibitor, we assessed the in vitro antiviral activity of Nilotinib against HCMV. Nilotinib exhibited a significant dose-dependent inhibition of the virus upon pre-incubation with the drug. Moreover, Nilotinib demonstrated a ∼4.5-fold higher antiviral activity against HCMV when compared to imatinib, with IC₅₀ values of 0.39 μM and 1.75 μM, respectively. No viral inhibition was found upon addition of the drugs after viral adsorption – compatible with inhibition of an early step of infection, involving viral binding/entry into the cell. These findings identify a promising new target for antiviral therapy, representing an alternative paradigm for treatment with compounds combining anti-cancer and antiviral activity. It remains to be determined if the anti-HCMV activity demonstrated for Nilotinib is of clinical relevance in patients undergoing SCT