Researchers report using structure-based design to create small molecules capable of preventing the viral protein Epstein–Barr Nuclear Antigen 1 from binding to DNA, thus blocking viral replication. The molecules inhibited the growth of tumors in cell lines and in patient-derived xenografts of Epstein–Barr virus–positive cancers.

Worldwide, more than 90% of adults are infected with Epstein–Barr virus (EBV), which is responsible for 1% to 2% of cancers, including some cases of nasopharyngeal carcinoma (NPC), gastric carcinoma, and Burkitt and Hodgkin lymphomas. Hoping to better treat EBV-positive cancers, investigators recently reported using structure-based drug design to create a new class of small molecules that inhibit Epstein–Barr Nuclear Antigen 1 (EBNA1), a protein needed for EBV replication.

“EBNA1 is an ideal drug target since it is uniquely viral and essential for tumorigenesis,” says Paul M. Lieberman, PhD, of the Wistar Institute in Philadelphia, PA, senior author of the paper.

The researchers used a combination of computer docking simulations and X-ray crystallography to screen 1,500 chemical fragments for the ability to bind to EBNA1′s DNA-binding domain to prevent the viral DNA replication and gene expression that drives proliferation and survival in EBV-positive cancer cells. These experiments yielded several promising fragments, which the investigators modified to further improve performance. For example, they chemically merged two of the top fragments to produce VK-0497, a molecule with more than ten times the potency of either fragment alone.

Next, the investigators tested the activity of two of the most promising molecules—VK-1727 and VK-1850—and determined that they inhibited the proliferation of EBV-positive cells but not EBV-negative cells, demonstrating their selectivity. The researchers also assessed the efficacy of these inhibitors in cell lines and in two EBV-positive NPC patient-derived xenografts in mice. The molecules performed significantly better than did a vehicle control. In addition, VK-1850 inhibited tumor growth significantly more than either radiation or chemotherapy, which are the standard therapies for NPC.

Gary Ka-Leung Wong, PhD, of Hong Kong Baptist University, who was not involved in this study but has worked on developing EBNA1 inhibitors, says the next step will be to further characterize the safety of and immune responses to these molecules in mice. Before moving to human studies, “drug resistance and the effect of these small molecules on tumor metastasis will be important issues to address as well,” he adds.

Meanwhile, another small-molecule EBNA1 inhibitor, VK2019, which also emerged from this study but was not described in the paper, will soon progress to a phase I/IIa trial in patients with relapsed, metastatic NPC. Leigh Zawel, PhD, chief scientific officer of Cullinan Oncology, the company conducting the trial, says that this inhibitor's safety and efficacy profile in several mouse models of NPC was encouraging and that prolonged exposure to the agent did not result in the emergence of drug resistance, making it a promising drug candidate.

Although the focus of the current trial is NPC, “we envision that an EBNA1 drug could be used to treat all EBV-positive cancers,” says lead author Troy Messick, PhD, also of the Wistar Institute. “If the safety profile of the drug warrants it, we could also imagine it being used as a prophylactic treatment in high-risk populations.”

Lawrence Young, PhD, of the University of Warwick in the UK, notes that a novel treatment for advanced NPC would be particularly welcome in southern China and southeast Asia, where “it is a very common tumor that often presents at a late stage, when current treatment options are limited.” –Kristin Harper

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.