Arno Therapeutics, Inc. a clinical stage biopharmaceutical company focused on developing therapeutics in cancer and other life threatening diseases, has announced that in-vitro data for its investigational agent AR-12 (also referred to as OSU-03012) generated by the Viral Special Pathogens Branch of the U.S. Centers for Disease Control and Prevention (CDC) was published online in the journal Antiviral Research.
The AR-12 data generated by the CDC, and published by Dr. Emma L. Mohr and colleagues in the article titled "Inhibitors of cellular kinases with broad-spectrum antiviral activity for hemorrhagic fever viruses," are part of a larger kinase screening program evaluating a series of compounds for potential activity against certain hemorrhagic fever viruses. The data demonstrate in-vitro activity of AR-12 against the Ebola (EBOV), Marburg, Lassa and Nipah hemorrhagic fever viruses. The concentration (ED50) of AR-12 that was found to inhibit the replication of these viruses was approximately 0.3 to 0.5 micromolar, and the cytoxic concentration (CC50) of AR-12 against the cell lines which the various viruses were grown in was approximately 5.7-8.2 micromolar with a calculated selectivity index (CC50/ED50) of 11-23 for the viral strains tested. [1]
Alex Zukiwski, MD, Chief Executive Officer of Arno Therapeutics, commented, "We are very encouraged by the CDC data demonstrating the in-vitro activity of AR-12 in Ebola, Marburg, Lassa and Nipah viruses. The concentrations of AR-12 which demonstrated activity against these four hemorrhagic fever viruses were approximately 10% of the plasma concentration achieved in a previous Phase 1 oncology study of AR-12. These data, along with antiviral data from other sources, provide rationale for further in-vitro and in-vivo evaluation of AR-12 against a number of viral pathogens."
Viruses rely on the underlying host cell machinery for viable viral replication. Multiple viral pathogens have evolved mechanisms to utilize (e.g. enhancement of protein folding) and subvert the host protein quality control machinery (e.g. the unfolded protein response, or UPR) to produce massive amounts of viral proteins, thereby enabling the completion of the viral life cycle.
A recent article published in the Journal of Cellular Physiology evaluated the impact of AR-12 on the expression of key host proteins involved in viral replication. The broad based antiviral activity exhibited by AR-12 is thought to be secondary to a unique mechanism of action which targets certain host cell processes that have been "hijacked" during viral replication. Investigation of AR-12 demonstrated that AR-12 suppresses expression of the GRP78 (BiP/HSPA5) chaperone, which is a key regulator of the UPR.[2] Further investigation demonstrated that AR-12 also impacts other key protein chaperones including HSP70 and HSP90[3] both of which play important roles in viral replication. GRP78, HSP70 and HSP90 are each known to have substantial effect on viral replication. [4,5,6]
Dr. Zukiwski added, "Targeting the host mechanisms involved in viral replication may allow for broad spectrum antiviral activity. The known safety profile of AR-12 may allow for combination therapies to be used, which together may provide a mechanism to circumvent antiviral resistance mechanisms or prevent them from developing. We look forward to further investigating the activity of AR-12 in the infectious disease setting."